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Sample records for anaplastic large t-cell

  1. Extreme neutrophil granulocytosis in a patient with anaplastic large cell lymphoma of T-cell lineage

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    Engsig, Frederik Neess; Møller, Michael Boe; Hasselbalch, Hans K

    2007-01-01

    We describe a 47-year-old male admitted with fever and extreme neutrophil granulocytosis (up to 80 x 10(9)/L). All microbiology tests and test for autoimmune disease were negative. CT scan showed pulmonary infiltrates bilaterally, mediastinal lymphadenopathy and splenomegaly. Conventional...... led to a diagnosis of anaplastic large cell lymphoma (ALCL) of T-cell lineage. Involvement of peripheral blood with leukemoid reaction is a rare manifestation of ALCL. This case emphasizes the importance of immunophenotyping in unexplained extreme granulocytosis....

  2. A Case of an Unusually Aggressive Cutaneous Anaplastic Large T-Cell Lymphoma in an HIV Patient Treated with CHOP

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    Jorge Hurtado-Cordovi

    2011-01-01

    Full Text Available Anaplastic large cell lymphoma (ALCL is the second most common malignancy of T-cell phenotype. This case report describes an unusual rapidly progressing cutaneous anaplastic large T-cell lymphoma in an HIV patient. Our patient is a twenty-year-old African American male with perinatally acquired HIV who presented with a 2×2 centimeter necrotic lesion in the right 1st toe; however, 2-3 weeks later multiple smaller lesions appeared on the anterior aspect of the right foot, ankle, and thigh. Biopsy showed cells strongly positive for CD3 and CD30 and negative for CD56 and the ALK gene product. CT of the chest, abdomen, and pelvis was negative for extracutaneous involvement favoring cutaneous ALCL. Patient was treated with 6 cycles of CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone chemotherapy and went into complete remission. Due to the aggressive course that this malignancy follows in HIV patients we suggest prompt treatment with systemic therapy.

  3. Extrinsic apoptotic pathways: A new potential "Target" for more sufficient therapy in a case of cutaneous anaplastic large CD30+ ALK-T--cell lymphoma

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    Georgi Tchernev

    2011-01-01

    Full Text Available The primary cutaneous T-cell lymphomas (CTCL represent a clonal T-lymphocyte proliferation infiltrating the skin. CD30+ T-cell lymphomas present clinically as nodules with a diameter between 1 and 15 cm, mostly in elderly patients. The role of the CD30 molecule in patients suffering from T-cell lymphomas is not completely clear yet. The signal transduction pathway which includes CD30 seems to play a key role in tumor progression. In certain forms of T-cellular lymphomas, the interaction between CD30/CD30-ligand is able to provoke apoptosis of the "tumor lymphocytes". The modern conceptions of the pathogenesis of T-cell lymphomas include disorders in the pathways involved in programmed cellular death and disregulation in the expression of certain of its regulatory molecules. We are presenting an unusual case of a female patient with a primary cutaneous form of CD30 + /ALK− anaplastic large T-cell lymphoma. Upon the introduction of systemic PUVA, (psoralen plus ultraviolet light radiation combined with beam therapy, a complete remission could be noticed. Eight months later, we observed a local recurrence, which was overcome by CHOP chemotherapy (Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin, Vincristin (Oncovin®, Predniso(lon. Six months later, new cutaneous lesions had been noticed again. A new therapeutic hope for the patients with anaplastic large CTCL is actually based on the influence of the activity of the different apoptotic pathways. Death ligands, including tumor necrosis factor (TNF-α, CD95L/FasL, and TRAIL, mediate also some important safeguard mechanisms against tumor growth in patients with CD30 + cutaneous anaplastic large T-cell lymphomas and critically contribute to lymphocyte homeostasis.

  4. TARC, a CC chemokine, is frequently expressed in classic Hodgkin's lymphoma but not in NLP Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma

    NARCIS (Netherlands)

    Peh, SC; Kim, LH; Poppema, S

    Thymus and activation-regulated chemokine (TARC) has been identified as a lymphocyte-directed CC chemokine that attracts activated T-helper type 2 (Th2) cells in humans. Recent studies showed that the T cells surrounding Reed-Sternberg cells in Hodgkin's lymphomas (HL) are Th2 type. Anaplastic large

  5. Synchronous meningioma and anaplastic large cell lymphoma.

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    Colen, Chaim B; Rayes, Mahmoud; Kupsky, William J; Guthikonda, Murali

    2010-06-01

    Synchronous primary brain tumors are exceedingly rare. When they occur, most cases are associated with metastatic disease. To the best of our knowledge, we report the first case of an atypical meningioma infiltrated by a T-cell-primary central nervous system lymphoma (PCNSL), specifically anaplastic large cell lymphoma (ALCL). We present a novel, unifying, plausible mechanism for its origin based on theories in the current literature. A 65-year-old man with a history of near-total resection of atypical meningioma presented with a complaint of progressive headaches. Imaging revealed recurrent tumor. Left frontal-temporal craniotomy with near-total tumor resection followed by radiation was performed. Recurrent symptomatic tumor led to repeat left frontotemporal craniotomy with tumor resection and partial anterior temporal lobectomy. Part of the specimen showed predominantly fibrotic neoplasm composed of nests and whorls of meningothelial cells, highlighted by epithelial membrane antigen (EMA) staining. The remainder of the specimen consisted of densely cellular neoplasm centered in connective tissue, including areas involved by meningioma. This tumor was composed of moderately large lymphoid cells with large nuclei, prominent nucleoli, and amphophilic cytoplasm. These cells were strongly immunoreactive for CD3 and CD30 but remained unstained with EMA, anaplastic lymphoma kinase-1 (ALK-1), CD15 or cytotoxic associated antigen TIA-1. Smaller mature lymphocytes, chiefly T-cells, were intermixed. The morphologic and immunohistochemical features were considered typical of anaplastic large T-cell lymphoma. The pathogenesis of this association may have been due to radiation-mediated breakdown of the blood-brain barrier with subsequent T-cell infiltration and proliferation. We advocate aggressive resection and long-term surveillance for individuals with metastasis, especially higher-grade neoplasms that receive radiotherapy.

  6. Primary cutaneous anaplastic large-cell lymphoma.

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    Perry, Edward; Karajgikar, Jay; Tabbara, Imad A

    2013-10-01

    Since the recognition of the anaplastic large-cell lymphomas in the 1980s, much has been learned about the diagnosis, clinical presentation, and treatment of these malignant conditions. The systemic and primary cutaneous types of anaplastic large cell lymphomas have been differentiated on clinical and immunophenotypical findings, but further research is required to elucidate their exact etiologies and pathogeneses. Primary cutaneous anaplastic large-cell lymphoma has a 95% disease-specific 5-year survival, owing partly to the relatively benign course of the disease and partly to the variety of effective treatments that are available. As with many other oncological diseases, new drugs are continually being tested and developed, with immunotherapy and biological response modifiers showing promise.

  7. Dual anaplastic large cell lymphoma mimicking meningioma: A case report

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    Kim, Keun Ho; Kim, Ki Hwan; Lee, Ghi Jai; Lee, Hye Kyung; Shim, Jae Chan; Lee, Kyoung Eun; Suh, Jung Ho [Seoul Paik Hospital, Inje University College of Medicine, Seoul (Korea, Republic of); Lee, Chae Heuck [Dept. of Neurosurgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang (Korea, Republic of)

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a rare T cell lymphoma composed of CD30-positive lymphoid cells. Most ALCLs present as nodal disease, with skin, bone, soft tissue, lung, and liver as common extranodal sites. ALCL rarely occurs in the central nervous system and is even more infrequent in the dura of the brain. We report a case of dural-based ALCL secondary to systemic disease in a 17-year-old male that mimicked meningioma on magnetic resonance imaging and angiography.

  8. Primary cutaneous anaplastic large cell lymphoma masquerading as large pyogenic granuloma

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    Anupama Bains

    2016-01-01

    Full Text Available Primary cutaneous anaplastic large cell lymphoma (pcALCL forms 9% of the cutaneous T-cell lymphomas. It usually presents as solitary reddish brown ulcerating nodule or indurated plaque. Sometimes, it mimics other dermatological diseases such as eczema, pyoderma gangrenosum, pyogenic granuloma, morphea, and squamous cell carcinoma. Our case presented with large pyogenic granuloma like lesion with regional lymphadenopathy. Since pcALCL is rare, one can misdiagnose such cases and therefore high index of suspicion is necessary.

  9. MicroRNA Expression Profiling Identifies Molecular Diagnostic Signatures for Anaplastic Large Cell Lymphoma

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    Liu, Cuiling; Iqbal, Javeed; Teruya-Feldstein, Julie

    2013-01-01

    Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9......) that differentiates ALK(-) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17∼92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway....... angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated...

  10. ALK signaling and target therapy in anaplastic large cell lymphoma

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    Fabrizio eTabbo

    2012-05-01

    Full Text Available The discovery by Morris SW et al. in 1994 of the genes contributing to the t(2;5(p23;q35 translocation has put the foundation for a molecular based recognition of Anaplastic Large Cell Lymphoma (ALCL and pointed out the need for a further stratification of T-cell neoplasia. Likewise the detection of ALK genetic lesions among many human cancers has defined unique subsets of cancer patients, providing new opportunities for innovative therapeutic interventions. The objective of this review is to appraise the molecular mechanisms driving ALK-mediated transformation, and to maintain the neoplastic phenotype. The understanding of these events will allow the design and implementation of novel tailored strategies for a well-defined subset of cancer patients.

  11. Pathobiology of Anaplastic Large Cell Lymphoma

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    Pier Paolo Piccaluga

    2010-01-01

    Full Text Available The authors revise the concept of anaplastic large cell lymphoma (ALCL in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated with special reference to the cytological spectrum that is indeed characteristic of the tumor. The phenotype is reported in detail: the expression of the ALK protein as well as the chromosomal abnormalities is discussed with their potential pathogenetic implications. The clinical features of ALCL are presented by underlining the difference in terms of response to therapy and survival between the ALK-positive and ALK-negative forms. Finally, the biological rationale for potential innovative targeted therapies is presented.

  12. Post transplant anaplastic large T-cell lymphoma

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    Azhir Afshin

    2009-01-01

    Full Text Available Post transplant lymphoproliferative disorders (PTLD are a heterogeneous group of lymphoid proliferation that ranges from polyclonal hyperplasia to monoclonal malignant lym-phoma. We report a 13-year-old boy who was diagnosed with PTLD in February 2007 after 3 1/2 years of deceased renal transplantation. We treated him with an adapted ACVBP (doxorubicin, cyclo-phosphamide, vincristine, bleomycin and prednisone regimen. He responded well to the chemo-therapy without deterioration of graft function.

  13. [A case of primary central nervous system anaplastic lymphoma kinase positive anaplastic large cell lymphoma manifested as a unilateral pachymeningits].

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    Fujisawa, Etsuco; Shibayama, Hidehiro; Mitobe, Fumi; Katada, Fumiaki; Sato, Susumu; Fukutake, Toshio

    2017-11-25

    There have been 23 reports of primary central nervous system anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma in the literature. Here we report the 24th case of a 40-year-old man who presented with occipital headache for one month. His contrast-enhanced brain MRI showed enhancement around the right temporal lobe, which suggested a diagnosis of hypertrophic pachymeningitis. He improved with steroid therapy. After discharge, however, he was readmitted with generalized convulsive seizures. Finally, he was diagnosed as primary central nervous system ALK-positive anaplastic large cell lymphoma by brain biopsy. Primary central nervous system lymphoma invading dura matter can rarely manifests as a unilateral pachymeningitis. Therefore, in case of pachymeningitis, we should pay attention to the possibility of infiltration of lymophoma with meticulous clinical follow-up.

  14. Malignant transformation of mature T cells after gammaretrovirus mediated transfer of nucleophosmin-anaplastic lymphoma kinase oncogene

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    Ashok Kumar

    2015-01-01

    Full Text Available Background: Gene therapy has been in use to cure hereditary and acquired diseases by incorporating the desired gene into the cells with the help of gammaretroviral vectors. Despite the success of this therapy in X-linked severe combined immunodeficiency syndrome, few patients developed leukemia as a major adverse event due to retroviral insertional mutagenesis within stem cells. In experimental animals also, retroviral-mediated gene transfer technique resulted in the development of leukemia. On the other hand, evidence suggests that mature T cells (TC are relatively resistant to transformation even after retroviral-mediated transfer of potent oncogenes Tcl1, ΔTrkA and LMO2 with no reported side effects yet. Aims: To further address the safety issue for TC use in gene therapy, this study investigated susceptibility of mature polyclonal TC to malignant transformation by the retroviral-mediated transfer of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK oncogene. Materials and Methods: Wild-type mature TC, isolated from C57BL/6 donor mice (genetic background Ly5.1 were transduced with gamma-retroviral vectors encoding the potent TC oncogene NPM-ALK or the control vector enhanced green fluorescent protein eGFP. The cells were then transplanted into RAG-1 deficient recipient mice (genetic background Ly5.2. Results: Two out of five mice from NPM-ALK oncogene group developed leukemia/lymphoma after latency periods (153 and 250 days, respectively. None of the mice from the control group developed any malignancy throughout the observational period. Conclusion: Mature polyclonal TC are relatively susceptible to malignant transformation after gamma-retroviral mediated transfer of NPM-ALK oncogene; hence safety of TC use in gene therapy should be further investigated to avoid the possible side-effect of development of leukemia/lymphoma.

  15. Skin involvement as the first manifestation of breast implant-associated anaplastic large cell lymphoma.

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    Alcalá, Rebeca; Llombart, Beatriz; Lavernia, Javier; Traves, Víctor; Guillén, Carlos; Sanmartín, Onofre

    2016-07-01

    Breast implant-associated anaplastic large cell lymphoma (ALCL) is a newly described clinical and pathologic entity that typically presents as seroma in the fibrous scar around the implant. Less frequently, it presents as a solid peri-implant mass, and there have been no reports to date of cutaneous lesions as the presenting manifestation. We report the case of a 56-year-old woman with a history of bilateral breast reconstruction following breast cancer of the right breast who consulted with several papules on the right breast suggestive of metastasis. Histopathology showed a proliferation of large epithelioid lymphocytes with highly pleomorphic cells and nuclei. The neoplastic cells were CD15 and CD30 positive and ALK-1 negative. The epithelial markers were all negative except for epithelial membrane antigen (EMA), which was weakly positive. Molecular analysis showed monoclonal T-cell receptor γ gene rearrangement, confirming a diagnosis of breast implant-associated ALCL. The non-specific morphology of the skin lesions, the epithelioid nature of the neoplastic cells and the expression of EMA can lead to an erroneous diagnosis of skin metastases from a poorly differentiated adenocarcinoma of the breast. We recommend immunohistochemical staining for CD30 and ALK-1 for patients with breast implants who develop anaplastic lesions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Large anaplastic spinal B-cell lymphoma in a cat.

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    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown.

  17. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma

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    Heidegger S

    2014-06-01

    Full Text Available Simon Heidegger,1 Ambros Beer,2 Eva Geissinger,3 Andreas Rosenwald,3 Christian Peschel,1 Ingo Ringshausen,1 Ulrich Keller11III Medical Department, 2Nuclear Medicine Department, Technische Universität München, Munich, Germany; 3Institute of Pathology, University of Würzburg, Würzburg, GermanyAbstract: Anaplastic large cell lymphoma (ALCL is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone. However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.Keywords: anaplastic large cell lymphoma (ALCL, refractory/relapsed lymphoma, anti-CD30 drug conjugate, DHAP

  18. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma.

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    Heidegger, Simon; Beer, Ambros J; Geissinger, Eva; Rosenwald, Andreas; Peschel, Christian; Ringshausen, Ingo; Keller, Ulrich

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.

  19. High expression of Mcl-1 in ALK positive and negative anaplastic large cell lymphoma

    NARCIS (Netherlands)

    Rust, R; Harms, G; Blokzijl, T; Boot, M; Diepstra, A; Kluiver, J; Visser, L; Peh, SC; Lim, M; Kamps, WA; Poppema, S; van den Berg, Anke

    Aim: To gain more insight into the genes involved in the aetiology and pathogenesis of anaplastic large cell lymphoma (ALCL). Methods: Serial analysis of gene expression ( SAGE) was undertaken on the CD4+ALK+ ( anaplastic lymphoma kinase positive) ALCL derived cell line Karpas299 and as comparison

  20. Change in the diagnosis from classical Hodgkin's lymphoma to anaplastic large cell lymphoma by 18F flourodeoxyglucose positron emission tomography/computed tomography: Importance of recognising disease pattern on imaging and immunohistochemistry

    International Nuclear Information System (INIS)

    Senthil, Raja; Mohapatra, Ranjan Kumar; Sampath, Mouleeswaran Koramadai; Sundaraiya, Sumati

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) is a rare type of nonHodgkin's lymphoma (NHL), but one of the most common subtypes of T-cell lymphoma. It is an aggressive T-cell lymphoma, and some ALCL may mimic less aggressive classical HL histopathlogically. It may be misdiagnosed unless careful immunohistochemical examination is performed. As the prognosis and management of these two lymphomas vary significantly, it is important to make a correct diagnosis. We describe a case who was diagnosed as classical HL by histopathological examination of cervical lymph node, in whom 18 F-flouro deoxyglucose positron emission tomography/computed tomography appearances were unusual for HL and warranted review of histopathology that revealed anaplastic lymphoma kinase-1 negative anaplastic large T-cell lymphoma, Hodgkin-like variant, thereby changing the management

  1. Anaplastic lymphoma kinase negative anaplastic large cell lymphoma of hard palate as first clinical manifestation of acquired immune deficiency syndrome

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    Anjali Narwal

    2016-01-01

    Full Text Available Anaplastic large cell lymphoma (ALCL is an uncommon disease, accounting for <5% of all cases of non-Hodgkin's lymphoma. We report a case of 48-year-old male who presented a clinically benign swelling in the right anterior palatal region since last 2 months. Radiographic evaluation showed no bone loss in palatal area. Histological and radiological examination was in favor of a peripheral reactive lesion like pyogenic granuloma or a benign salivary gland tumor. Immunohistochemistry confirmed the diagnosis of anaplastic lymphoma kinase-negative (ALK(− ALCL. Further laboratory tests ELISA for human immunodeficiency virus (HIV and CD4 cell count was done which showed positivity for HIV. To the best of our knowledge, it is the first case of ALK(− ALCL in the hard palate presenting as the first clinical manifestation of acquired immune deficiency syndrome.

  2. Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis – a review

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    Fernando Peixoto Ferraz de Campos

    2013-10-01

    Full Text Available Anaplastic large cell lymphoma (ALCL, described less than 30 years ago by Karl Lennert and Herald Stein in Kiel, West Germany, is a T-cell or null non-Hodgkin lymphoma, with distinctive morphology (hallmark cells, prominent sinus and/or perivascular growth pattern, characteristic immunophenotype (CD30+, cytotoxic granules protein+, CD3–/+ and specific genetic features as translocations involving the receptor tyrosine kinase called anaplastic lymphoma kinase (ALK on 2p23 and variable partners genes, which results in the expression of ALK fusion protein. The absence of ALK expression is also observed and is associated with poorer prognosis that seen with ALK expression. ALK-negative ALCL is more frequent in adults, with both nodal and extra nodal clinical presentation and includes several differential diagnoses with other CD30+ lymphomas. Liver involvement by ALCL is rare and is generally seen as mass formation; the diffuse pattern of infiltration is even more unusual. The authors present a case of a 72-year-old man who presented clinical symptoms of acute hepatic failure. The patient had a long history of alcohol abuse and the diagnosis of alcoholic hepatitis was highly considered, although the serum lactic dehydrogenase (LDH value was highly elevated. The clinical course was fulminant leading to death on the fourth day of hospitalization. Autopsy demonstrated diffuse neoplastic hepatic infiltration as well as splenic, pulmonary, bone marrow, and minor abdominal lymph nodes involvement by the tumor. Based on morphological, immunophenotypical, and immunohistochemical features, a diagnosis of ALK- negative ALCL was concluded. When there is marked elevation of LDH the possibility of lymphoma, ALCL and other types, should be the principal diagnosis to be considered.

  3. Radiation Therapy for Primary Cutaneous Anaplastic Large Cell Lymphoma: An International Lymphoma Radiation Oncology Group Multi-institutional Experience

    International Nuclear Information System (INIS)

    Million, Lynn; Yi, Esther J.; Wu, Frank; Von Eyben, Rie; Campbell, Belinda A.; Dabaja, Bouthaina; Tsang, Richard W.; Ng, Andrea; Wilson, Lynn D.; Ricardi, Umberto; Kirova, Youlia; Hoppe, Richard T.

    2016-01-01

    Purpose: To collect response rates of primary cutaneous anaplastic large cell lymphoma, a rare cutaneous T-cell lymphoma, to radiation therapy (RT), and to determine potential prognostic factors predictive of outcome. Methods and Materials: The study was a retrospective analysis of patients with primary cutaneous anaplastic large cell lymphoma who received RT as primary therapy or after surgical excision. Data collected include initial stage of disease, RT modality (electron/photon), total dose, fractionation, response to treatment, and local recurrence. Radiation therapy was delivered at 8 participating International Lymphoma Radiation Oncology Group institutions worldwide. Results: Fifty-six patients met the eligibility criteria, and 63 tumors were treated: head and neck (27%), trunk (14%), upper extremities (27%), and lower extremities (32%). Median tumor size was 2.25 cm (range, 0.6-12 cm). T classification included T1, 40 patients (71%); T2, 12 patients (21%); and T3, 4 patients (7%). The median radiation dose was 35 Gy (range, 6-45 Gy). Complete clinical response (CCR) was achieved in 60 of 63 tumors (95%) and partial response in 3 tumors (5%). After CCR, 1 tumor recurred locally (1.7%) after 36 Gy and 7 months after RT. This was the only patient to die of disease. Conclusions: Primary cutaneous anaplastic large cell lymphoma is a rare, indolent cutaneous lymphoma with a low death rate. This analysis, which was restricted to patients selected for treatment with radiation, indicates that achieving CCR was independent of radiation dose. Because there were too few failures (<2%) for statistical analysis on dose response, 30 Gy seems to be adequate for local control, and even lower doses may suffice.

  4. High intratumoral macrophage content is an adverse prognostic feature in anaplastic large cell lymphoma

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    Pedersen, Martin B; Danielsen, Allan V; Hamilton-Dutoit, Stephen J

    2014-01-01

    AIMS: Macrophage infiltration has been associated with prognosis in several cancers, including lymphoma, but has not been assessed systematically in anaplastic large cell lymphoma (ALCL). The aim of the study was to correlate expression of the macrophage-associated antigens CD68 and CD163 with pr...

  5. Spinal cord compression caused by anaplastic large cell lymphoma in an HIV infected individual

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    Kumar Susheel

    2010-01-01

    Full Text Available Lymphomas occur with an increased frequency in patients with Human Immunodeficiency Virus (HIV infection. These are usually high-grade immunoblastic lymphomas and primary central nervous system lymphomas. Anaplastic large cell lymphoma (ALCL is a distinct type of non-Hodgkin′s lymphoma. It is uncommon in HIV infected individuals. We describe here an uncommon presentation of this relatively rare lymphoma in the form of spinal cord compression syndrome in a young HIV infected individual.

  6. Anaplastic large-cell lymphoma with florid granulomatous reaction: A case report and review of literature

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    Balamurugan S

    2009-01-01

    Full Text Available Granulomatous reactions have been reported in association with lymphomas, more often with Hodgkins disease than with Non-Hodgkins Lymphoma. Not many reports are available on the association of anaplastic large-cell lymphoma with sarcoid-type granuloma. Herein, we report a case of an elderly female with generalized lymphadenopathy who had a florid granulomatous reaction almost masking the lymphoma cells in the lymph node biopsy. A detailed clinical history, careful histological examination and immunohistochemistry helped in attaining the correct diagnosis.

  7. Novel Technique for Sampling of Breast Implant–associated Seroma in Anaplastic Large Cell Lymphoma

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    T’Kindt, Johan; Mertens, Marianne; Colpaert, Steven D. M.

    2016-01-01

    Summary: We describe a novel technique for the sampling of breast implant–associated seroma. Using a blunt-tip lipofilling cannula, we have the freedom of movement to sample all fluid collections and prevent the misfortunes of damaging the implant. Also, we have demonstrated the inability of the Coleman style I lipofilling cannula to perforate a silicone breast implant. This practical and reliable technique will prove to be useful in managing the breast implant–associated seroma, especially with the rising incidence of the anaplastic large cell lymphoma, where the sampling of seroma is mandatory. PMID:27200250

  8. Cardiac Tamponade Associated with the Presentation of Anaplastic Large Cell Lymphoma in a 2-Year-Old Child

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    Gema Mira-Perceval Juan

    2015-01-01

    Full Text Available The anaplastic large cell lymphoma is a rare entity in pediatric patients. We present an unusual case of pericardial involvement, quite uncommon as extranodal presentation of this type of disorder, that provoked a life-risk situation requiring an urgent pericardiocentesis. To our knowledge, this is the first report on a child with pericardial involvement without an associated cardiac mass secondary to anaplastic large cell lymphoma in pediatric age. We report the case of a 21-month-old Caucasian male infant with cardiac tamponade associated with the presentation of anaplastic large cell lymphoma. Initially, the child presented with 24-day prolonged fever syndrome, cutaneous lesions associated with hepatomegaly, inguinal adenopathies, and pneumonia. After a 21-day asymptomatic period, polypnea and tachycardia were detected in a clinical check-up. Chest X-ray revealed a remarkable increase of the cardiothoracic index. The anaplastic large cell lymphoma has a high incidence of extranodal involvement but myocardial or pericardial involvements are rare. For this reason, we recommend a close monitoring of patients with a differential diagnosis of anaplastic large cell lymphoma.

  9. Leukaemic presentation of small cell variant anaplastic large cell lymphoma: report of four cases.

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    Bayle, C; Charpentier, A; Duchayne, E; Manel, A M; Pages, M P; Robert, A; Lamant, L; Dastugue, N; Bertrand, Y; Dijoud, F; Emile, J F; Machover, D; Brugiéres, L; Delsol, G

    1999-03-01

    We report four cases of a rare subtype of CD30-positive anaplastic large cell lymphoma (ALCL) with a predominant small cell component (small cell variant of ALCL) presenting with a leukaemic feature. Lymph node biopsy showed malignant cells of varying size with a predominant population of small to medium-sized malignant cells associated with large anaplastic cells strongly positive for CD30 and epithelial membrane antigen (EMA). Both large and small cells were reactive with antibody ALK1, which recognizes the chimaeric NPM-ALK protein associated with the t(2;5)(p23;q35). All patients presented with hyperleucocytosis with atypical small lymphocytes. Bone marrow involvement was detected on both aspirate and bone marrow trephine where scattered malignant cells were only demonstrated by immunostaining for CD30 and ALK protein. Atypical cells in peripheral blood, lymph node and skin biopsies showed a T or null cell phenotype. Cytogenetic analysis of blood, bone marrow and/or lymph node revealed the t(2:5)(p23;q35) characteristic of ALCL. The patients responded to chemotherapy but showed early relapse without abnormal cells in peripheral blood. This report shows that the small cell variant of ALCL may have a leukaemic presentation with peripheral blood involvement by atypical lymphocytes and provides evidence that, in the small cell variant of ALCL, the small cell component is a part of the malignant clone.

  10. Anaplastic Large-Cell Lymphoma in a Child with Type I Diabetes and Unrecognised Coeliac Disease

    Directory of Open Access Journals (Sweden)

    Jemima Sharp

    2012-01-01

    Full Text Available Screening for coeliac disease is recommended for children from certain risk groups, with implications for diagnostic procedures and dietetic management. The risk of a malignant complication in untreated coeliac disease is not considered high in children. We present the case of a girl with type I diabetes who developed weight loss, fatigue, and inguinal lymphadenopathy. Four years before, when she was asymptomatic, a screening coeliac tTG test was positive, but gluten was not eliminated from her diet. Based on clinical examination, a duodenal biopsy, and an inguinal lymph node biopsy were performed, which confirmed both coeliac disease and an anaplastic large-cell lymphoma. HLA-typing demonstrated that she was homozygous for HLA-DQ8, which is associated with higher risk for celiac disease, more severe gluten sensitivity, and diabetes susceptibility. She responded well to chemotherapy and has been in remission for over 4 years. She remains on a gluten-free diet. This is the first case reporting the association of coeliac disease, type I diabetes, and anaplastic large-cell lymphoma in childhood. The case highlights the malignancy risk in a genetically predisposed individual, and the possible role of a perpetuated immunologic response by prolonged gluten exposure.

  11. Association of inclusion body myositis with T cell large granular lymphocytic leukaemia

    DEFF Research Database (Denmark)

    Greenberg, Steven A; Pinkus, Jack L; Amato, Anthony A

    2016-01-01

    SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we...... on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects...... prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD...

  12. Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma

    Science.gov (United States)

    Clemens, Mark W.; Medeiros, L. Jeffrey; Butler, Charles E.; Hunt, Kelly K.; Fanale, Michelle A.; Horwitz, Steven; Weisenburger, Dennis D.; Liu, Jun; Morgan, Elizabeth A.; Kanagal-Shamanna, Rashmi; Parkash, Vinita; Ning, Jing; Sohani, Aliyah R.; Ferry, Judith A.; Mehta-Shah, Neha; Dogan, Ahmed; Liu, Hui; Thormann, Nora; Di Napoli, Arianna; Lade, Stephen; Piccolini, Jorge; Reyes, Ruben; Williams, Travis; McCarthy, Colleen M.; Hanson, Summer E.; Nastoupil, Loretta J.; Gaur, Rakesh; Oki, Yasuhiro; Young, Ken H.

    2016-01-01

    Purpose Breast implant–associated anaplastic large-cell lymphoma (BI-ALCL) is a rare type of T-cell lymphoma that arises around breast implants. The optimal management of this disease has not been established. The goal of this study is to evaluate the efficacy of different therapies used in patients with BI-ALCL to determine an optimal treatment approach. Patients and Methods In this study, we applied strict criteria to pathologic findings, assessed therapies used, and conducted a clinical follow-up of 87 patients with BI-ALCL, including 50 previously reported in the literature and 37 unreported. A Prentice, Williams, and Peterson model was used to assess the rate of events for each therapeutic intervention. Results The median and mean follow-up times were 45 and 30 months, respectively (range, 3 to 217 months). The median overall survival (OS) time after diagnosis of BI-ALCL was 13 years, and the OS rate was 93% and 89% at 3 and 5 years, respectively. Patients with lymphoma confined by the fibrous capsule surrounding the implant had better event-free survival (EFS) and OS than did patients with lymphoma that had spread beyond the capsule (P = .03). Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014) than did patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. Conclusion Surgical management with complete surgical excision is essential to achieve optimal EFS in patients with BI-ALCL. PMID:26628470

  13. Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

    Science.gov (United States)

    Clemens, Mark W; Medeiros, L Jeffrey; Butler, Charles E; Hunt, Kelly K; Fanale, Michelle A; Horwitz, Steven; Weisenburger, Dennis D; Liu, Jun; Morgan, Elizabeth A; Kanagal-Shamanna, Rashmi; Parkash, Vinita; Ning, Jing; Sohani, Aliyah R; Ferry, Judith A; Mehta-Shah, Neha; Dogan, Ahmed; Liu, Hui; Thormann, Nora; Di Napoli, Arianna; DiNapoli, Arianna; Lade, Stephen; Piccolini, Jorge; Reyes, Ruben; Williams, Travis; McCarthy, Colleen M; Hanson, Summer E; Nastoupil, Loretta J; Gaur, Rakesh; Oki, Yasuhiro; Young, Ken H; Miranda, Roberto N

    2016-01-10

    Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a rare type of T-cell lymphoma that arises around breast implants. The optimal management of this disease has not been established. The goal of this study is to evaluate the efficacy of different therapies used in patients with BI-ALCL to determine an optimal treatment approach. In this study, we applied strict criteria to pathologic findings, assessed therapies used, and conducted a clinical follow-up of 87 patients with BI-ALCL, including 50 previously reported in the literature and 37 unreported. A Prentice, Williams, and Peterson model was used to assess the rate of events for each therapeutic intervention. The median and mean follow-up times were 45 and 30 months, respectively (range, 3 to 217 months). The median overall survival (OS) time after diagnosis of BI-ALCL was 13 years, and the OS rate was 93% and 89% at 3 and 5 years, respectively. Patients with lymphoma confined by the fibrous capsule surrounding the implant had better event-free survival (EFS) and OS than did patients with lymphoma that had spread beyond the capsule (P = .03). Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014) than did patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. Surgical management with complete surgical excision is essential to achieve optimal EFS in patients with BI-ALCL. © 2015 by American Society of Clinical Oncology.

  14. Primary CNS anaplastic diffuse large B-cell lymphoma mimicking undifferentiated metastatic tumors: a case report.

    Science.gov (United States)

    Yang, Tianyu; Belverud, Shawn; Yeh, Albert Y; Bandovic, Jela; Farmer, Peter; Woldenberg, Rona F; Demopoulos, Alexis; Schulder, Michael; Li, Jian Yi

    2010-02-01

    Primary central nervous system lymphoma (PCNSL) is a rare intracranial tumor, with an annual incidence of six per million population. Anaplastic variant of primary CNS diffuse large B-cell lymphoma is less common; to our knowledge, there is only one other case report in the world literature. We describe a 71 year old immunocompetent female without significant past medical history who presented with confusion and a homogeneously enhancing midline mass. The patient underwent craniotomy for tumor biopsy, followed by high-dose methotrexate-based chemotherapy despite a remarkably low performance status. Histologically, this tumor was composed of undifferentiated polymorphic tumor cells, multi-nucleated giant cells, extensive necrosis, and conspicuous mitotic activity, mimicking undifferentiated metastatic tumors. Immunohistochemical stains demonstrated immunopositivity of tumor cells for CD20, MUM-1, and BCL-6, and negative staining for CD3, CD10, and CD30. The clinical course, diagnostic workup, pathologic correlates, and treatment outcomes are described.

  15. T-cell/histiocyte-rich large B-cell lymphoma of stomach.

    Science.gov (United States)

    Barut, Figen; Kandemir, Nilufer Onak; Gun, Banu Dogan; Ozdamar, Sukru Oguz

    2016-07-01

    T-cell/histiocyte-rich large B-cell lymphoma is an unusually encountered lymphoid neoplasm of stomach with aggressive course, and is an uncommon morphologic variant of diffuse large B-cell lymphoma. An ulcerated mass, 7x5x1 cm in size was observed within the gastrectomy specimen of a 76-year-old female patient. In cross sections, besides mature lymphoid cells displaying T-cell phenotype, a neoplastic formation composed of large, pleomorphic atypical lymphoid cells with, prominent nucleoli, vesicular nuclei and abundant eosinophilic cytoplasm displaying B-cell phenotype were observed. Meanwhile, histiocyte-like mononuclear cells and Reed-Sternberg-like multinuclear cells expressing CD68 and Mac387 were also observed. The diagnosis of the case was T cell/histiocyte-rich large B-cell lymphoma. This rarely encountered neoplasm should be kept in mind in the differential diagnosis of primary gastric lymphomas.

  16. Hemophagocytic lymphohistiocytosis secondary to T-cell/histiocyte-rich large B-cell lymphoma

    Directory of Open Access Journals (Sweden)

    Katherine Devitt

    2014-01-01

    Full Text Available Hemophagocytic lymphohistiocytosis (HLH is a life-threatening clinical syndrome characterized by dysregulation of the immune system. Impaired function of cytotoxic T cells and natural killer cells is often seen, and T-cell malignancies represent most cases of lymphoma-associated HLH. HLH associated with B-cell lymphoma is rare. We describe a case of a 30-year-old man who presented with fever, splenomegaly, and hyperferritinemia. Bone marrow biopsy revealed T-cell/histiocyte-rich large B-cell lymphoma, a rare, aggressive B-cell malignancy. This case highlights the interplay between a pro-inflammatory cytokine microenvironment and tumor-mediated immune suppression, and addresses the importance of accurately diagnosing these entities for appropriate clinical management.

  17. Clinical and laboratory characteristics of systemic anaplastic large cell lymphoma in Chinese patients

    Directory of Open Access Journals (Sweden)

    Wang Yan-Fang

    2012-07-01

    Full Text Available Abstract Background Systemic anaplastic large cell lymphoma (S-ALCL is a rare disease with a highly variable prognosis and no standard chemotherapy regimen. Anaplastic lymphoma kinase (ALK has been reported as an important prognostic factor correlated with S-ALCL in many but not all studies. In our study, we retrospectively analyzed 92 patients with S-ALCL from the Peking University Lymphoma Center for clinical and molecular prognostic factors to make clear the role of ALK and other prognostic factors in Han Chinese S-ALCL. Results The majority of Chinese S-ALCL patients were young male patients (median age 26, male/female ratio 1.7 and the median age was younger than previous reports regardless of ALK expression status. The only statistically significant different clinical characteristic in S-ALCL between ALK positive (ALK+ and ALK negative (ALK- was age, with a younger median age of 22 for ALK+ compared with 30 for ALK-. However, when pediatric patients (≤18 were excluded, there was no age difference between ALK+ and ALK-. The groups did not differ in the proportion of males, those with clinical stage III/IV (49 vs 51% or those with extranodal disease (53 vs 59%. Of 73 evaluable patients, the 3-year and 5-year survival rates were 60% and 47%, respectively. Univariate analysis showed that three factors: advanced stage III/IV, lack of expression of ALK, and high Ki-67 expression, were associated with treatment failure in patients with S-ALCL. However, ALK expression correlated with improved survival only in patients younger than 14 years, while not in adult patients. In multivariate analysis, only clinical stage was an independent prognostic factor for survival. Expressions of Wilms tumor 1 (WT1 and B-cell lymphoma 2 protein (BCL-2 correlated with the expression of ALK, but they did not have prognostic significance. High Ki-67 expression was also a poor prognostic factor. Conclusions Our results show that ALK expression alone is not

  18. Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Michael J. Peluso

    2012-01-01

    Full Text Available Hemophagocytic syndrome (HPS arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL. This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified.

  19. Successful Treatment in a Child with Anaplastic Large Cell Lymphoma and Coexistence of Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    Margarita Baka

    2013-01-01

    Full Text Available A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL, whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months, pyrazinamide (the first 2 months, and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time.

  20. {sup 18}F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

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    Lee, Dong Yun; Lee, Jong Jin; Park, Seol Hoon; Chae, Sunyoung; Kim, Shin; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung; Ryu, Jinsook [Univ. of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2013-12-15

    Primary systemic anaplastic large cell lymphoma (ALCL) is divided into two entities according to the expression of anaplastic lymphoma kinase (ALK). We investigated {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET) findings in primary systemic ALCL according to ALK expression. Thirty-seven patients who had baseline PET before CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based chemotherapy were enrolled. Among them, patients who underwent interim and/or post-therapy PET were further investigated for the treatment response and survival analysis. Baseline PET was analyzed visually and semi-quantitatively using peak SUV, and interim and post-therapy PETs were visually analyzed. All cases were {sup 18}F-FDG-avid on baseline PET. The peak SUV of ALK-positive ALCL (n =16, 18.7±10.5) was higher than that of ALK-negative ALCL (n =21, 10.0±4.9) (P =0.006). In ALK-negative ALCL, complete response (CR) rate in negative-interim PET was higher than positive-interim PET (100 % vs 37.5 %, P=0.02); however, there was no such difference in ALK-positive ALCL (100 % vs 75 %, P =0.19). The 3-year progression-free survival (PFS) was not significantly different between ALK-positive and ALK-negative ALCL (72.7 % vs 47.6 %, P =0.34). In ALK-negative ALCL, negative interim and post-therapy PET patients had better 3-year PFS than positive interim (83.3 % vs 25.0 %, P =0.06) and post-therapy PET patients (70.0%vs 20.0 %, P =0.04). In contrast, ALK-positive ALCL had no such differences between PFS and PET results. On baseline PET, all cases showed {sup 18}F-FDG avidity, and ALK expression was related to higher {sup 18}F-FDG uptake. ALK-positive patients tend to have better PFS than ALK-negative patients. Negative-interim PET was a good indicator of CR, and interim or post-therapy PET was helpful for predicting the prognosis only in the ALK-negative group.

  1. Bacterial Biofilm Infection Detected in Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

    Science.gov (United States)

    Hu, Honghua; Johani, Khalid; Almatroudi, Ahmad; Vickery, Karen; Van Natta, Bruce; Kadin, Marshall E; Brody, Garry; Clemens, Mark; Cheah, Chan Yoon; Lade, Stephen; Joshi, Preeti Avinash; Prince, H Miles; Deva, Anand K

    2016-06-01

    A recent association between breast implants and the development of anaplastic large-cell lymphoma (ALCL) has been observed. The purpose of this study was to identify whether bacterial biofilm is present in breast implant-associated ALCL and, if so, to compare the bacterial microbiome to nontumor capsule samples from breast implants with contracture. Twenty-six breast implant-associated ALCL samples were analyzed for the presence of biofilm by real-time quantitative polymerase chain reaction, next-generation sequencing, fluorescent in situ hybridization, and scanning electron microscopy, and compared to 62 nontumor capsule specimens. Both the breast implant-associated ALCL and nontumor capsule samples yielded high mean numbers of bacteria (breast implant-associated ALCL, 4.7 × 10 cells/mg of tissue; capsule, 4.9 × 10 cells/mg of tissue). Analysis of the microbiome in breast implant-associated ALCL specimens showed significant differences with species identified in nontumor capsule specimens. There was a significantly greater proportion of Ralstonia spp. present in ALCL specimens compared with nontumor capsule specimens (p capsule specimens compared with breast implant-associated ALCL specimens (p < 0.001). Bacterial biofilm was visualized both on scanning electron microscopy and fluorescent in situ hybridization. This novel finding of bacterial biofilm and a distinct microbiome in breast implant-associated ALCL samples points to a possible infectious contributing cause. Breast implants are widely used in both reconstructive and aesthetic surgery, and strategies to reduce their contamination should be more widely studied and practiced. Risk, V.

  2. Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of ALK-Positive Anaplastic Large Cell Lymphoma.

    Science.gov (United States)

    Xu, Wendan; Kim, Ji-Won; Jung, Woo June; Koh, Youngil; Yoon, Sung-Soo

    2017-06-19

    Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant NPM-ALK fusion protein. Both mTOR inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated PI3K/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. Crizotinib combined with everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

  3. Sequential development of peripheral t-cell lymphoma post immunochemotherapy of diffuse large B cell lymphoma.

    Science.gov (United States)

    Wang, Jing-Wen; Chen, Jia-Yan; Lu, Chen; Tang, Xi

    2017-04-03

    Reports of sequential occurrence of two or more types of lymphoma are rare, especially when they involve different cell lineages. Herein, we report a rare case of sequential development of peripheral t-cell lymphoma following treatment of diffuse large B cell lymphoma. In a 73-year-old Chinese male patient, diffuse large B-cell lymphoma (DLBCL) was diagnosed in September 2011 based on the result of a tongue biopsy. Afterwards, he received rituximab combined with chemotherapy and local radiotherapy. Though he achieved completed remission, he had a new symptom of one enlarged left inguinal lymph node in November of 2015. A new biopsy was then performed. Immunohistochemistry and polymerase chain reaction (PCR) for gene rearrangements proved monoclonal T-cell lymphoma. We didn't detect EBV infection in either of two biopsies, nor any evidence of immune dysfunction complications. Sequential development of B-cell and T-cell malignancy in this patient maybe an example of treatment-related secondary lymphoma.

  4. Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma

    International Nuclear Information System (INIS)

    Gao, Ju; Yin, Minzhi; Zhu, Yiping; Gu, Ling; Zhang, Yanle; Li, Qiang; Jia, Cangsong; Ma, Zhigui

    2013-01-01

    Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the

  5. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

    Science.gov (United States)

    Neelapu, Sattva S; Locke, Frederick L; Bartlett, Nancy L; Lekakis, Lazaros J; Miklos, David B; Jacobson, Caron A; Braunschweig, Ira; Oluwole, Olalekan O; Siddiqi, Tanya; Lin, Yi; Timmerman, John M; Stiff, Patrick J; Friedberg, Jonathan W; Flinn, Ian W; Goy, Andre; Hill, Brian T; Smith, Mitchell R; Deol, Abhinav; Farooq, Umar; McSweeney, Peter; Munoz, Javier; Avivi, Irit; Castro, Januario E; Westin, Jason R; Chavez, Julio C; Ghobadi, Armin; Komanduri, Krishna V; Levy, Ronald; Jacobsen, Eric D; Witzig, Thomas E; Reagan, Patrick; Bot, Adrian; Rossi, John; Navale, Lynn; Jiang, Yizhou; Aycock, Jeff; Elias, Meg; Chang, David; Wiezorek, Jeff; Go, William Y

    2017-12-28

    In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10 6 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy

  6. The importance of Notch signaling in peripheral T-cell lymphomas

    DEFF Research Database (Denmark)

    Kamstrup, Maria Rørbæk; Biskup, Edyta; Gjerdrum, Lise Mette Rahbek

    2014-01-01

    Peripheral T-cell lymphomas (PTLs) represent an area of high medical need. Previously, we demonstrated high expression of Notch, a known oncogene, in primary cutaneous anaplastic large cell lymphoma (ALCL). In this study, we performed immunohistochemical staining for Notch1 in lymph nodes from PT...

  7. Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice.

    Science.gov (United States)

    Klebanoff, Christopher A; Gattinoni, Luca; Palmer, Douglas C; Muranski, Pawel; Ji, Yun; Hinrichs, Christian S; Borman, Zachary A; Kerkar, Sid P; Scott, Christopher D; Finkelstein, Steven E; Rosenberg, Steven A; Restifo, Nicholas P

    2011-08-15

    Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (γ(c)) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified. To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (T(CM)), effector memory (T(EM)), and stem cell memory (T(SCM)) subsets on the strength of tumor regression as well as the dose and type of clinically available γ(c) cytokines, including IL-2, IL-7, IL-15, and IL-21. We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γ(c) cytokine only moderately correlated with response. Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that γ(c) cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo. ©2011 AACR.

  8. Treatment of primary cutaneous anaplastic large cell lymphoma with superficial x-rays

    DEFF Research Database (Denmark)

    Jepsen, Malene E; Gniadecki, Robert

    2015-01-01

    The optimal radiation schedule for primary cutaneous anaplastic lymphoma (PCALCL) has not been investigated. We report here satisfactory outcomes of low-dose (16-20 Gy, 3-5 fractions), superficial X-ray radiation (40-50 kV) in a series of 10 patients with PCALCL. Only 1 patient developed a local ...... relapse during the median observation time of 25 months; complete remission was recorded in the other patients. This observation indicates that superficial, low dose X-ray therapy may provide a cost-effective alternative to the traditional 35-45 Gy schedules....

  9. T Cell/Histiocyte-Rich Large B Cell Lymphoma of the Thymus: A Diagnostic Pitfall

    Directory of Open Access Journals (Sweden)

    Jie Xu

    2016-01-01

    Full Text Available T cell/histiocyte-rich large B cell lymphoma (THRLBCL is predominantly a nodal disease, with extranodal involvement, such as bone marrow, spleen, and liver. However, primary THRLBCL has never been reported in the thymus in the English literature. Here we report a case of THRLBCL presenting as mediastinal mass and lymphadenopathy. Based on the frozen section diagnosis of “thymoma,” a 12 cm mass was excised. A year later she developed multiple enlarged lymph nodes and pulmonary nodules. Consultant review of the excised mediastinal mass showed scattered large atypical cells that were CD20+ and PAX-5+ and negative for pan-cytokeratin, AE1, and AE3, compatible with THRLBCL and excluding thymoma. The excised lymph nodes were replaced by diffuse infiltrate of small CD3+ lymphocytes and histiocytes with intermingled large CD20+ B lymphoma cells scattered throughout the section. A diagnosis of THRLBCL was made in lymph node, similar to previous thymic lesion. A clonal rearrangement of immunoglobulin heavy chain (IGH gene was detected, further supporting the diagnosis. This is the first reported case of THRLBCL in thymus. Correct recognition of this entity is critical, because of the difference in therapeutic impact on these patients.

  10. Large cell/anaplastic medulloblastoma with myogenic, melanotic and neuronal differentiation: A case report of a rare tumor

    Directory of Open Access Journals (Sweden)

    Amany A. Fathaddin

    2014-01-01

    Full Text Available Medulloblastoma is an embryonal neuroepithelial tumor of the cerebellum and is the most common malignant central nervous system tumor in children. Different histological variants and patterns have been described. The classic variant represents the majority of cases. This report describes a rare case of large cell/anaplastic medulloblastoma with myogenic, melanotic and neuronal differentiation arising in the cerebellum of a 3-year-old boy who presented with headache and vomiting. Magnetic resonance imaging demonstrated a heterogeneously enhanced lesion in the fourth ventricle. Surgical resection of the tumor was accomplished, but a residual tumor was left behind because of the involvement of the brainstem. Postoperatively, the patient received chemotherapy and radiotherapy. Currently, 20 months after treatment, the patient has survived without further progression. Pathological examination revealed a high grade primitive neuronal tumor with foci of myogenic features, melanin containing epithelial elements and ganglion-like cells, which were confirmed by immunohistochemistry.

  11. Locally advanced breast implant associated anaplastic large cell lymphoma: A case report of successful treatment with radiation and chemotherapy

    Directory of Open Access Journals (Sweden)

    Christopher Fleighton Estes

    2015-02-01

    Full Text Available The development of breast implant associated anaplastic large cell lymphoma (ALCL is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can become more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy.

  12. TIMP-I expression in anaplastic large cell lymphoma is usually restricted to macrophages and only seldom observed in tumour cells

    NARCIS (Netherlands)

    Rust, R; Blokzijl, T; Harms, G; Lim, M; Visser, L; Kamps, WA; Poppema, S; van den Berg, Anke

    Anaplastic large cell lymphomas (ALCLs) can be subdivided into two subgroups on the basis of their expression of the ALK protein. ALK protein expression leads to activation of signal transducer and activator of transcription (STAT) 3, which is more commonly expressed in ALK-positive than in

  13. Anaplastic carcinoma

    International Nuclear Information System (INIS)

    Parikh, D.M.; Agarwal, S.; Rao, R.S.

    1999-01-01

    Thyroid carcinoma (TC) is a slow growing tumor with an indolent course and has an excellent prognosis. However, a sharp contrast exists in the biological behavior of TC, which in its well-differentiated form is associated with long-term survival, but in its undifferentiated form is one of the most lethal neoplasms known. The anaplastic carcinoma (ANC) form has a fulminanat course with poor prognosis and almost invariably, a fatal outcome

  14. A nanocomplex that is both tumor cell-selective and cancer gene-specific for anaplastic large cell lymphoma

    Directory of Open Access Journals (Sweden)

    Zu Youli

    2011-01-01

    Full Text Available Abstract Background Many in vitro studies have demonstrated that silencing of cancerous genes by siRNAs is a potential therapeutic approach for blocking tumor growth. However, siRNAs are not cell type-selective, cannot specifically target tumor cells, and therefore have limited in vivo application for siRNA-mediated gene therapy. Results In this study, we tested a functional RNA nanocomplex which exclusively targets and affects human anaplastic large cell lymphoma (ALCL by taking advantage of the abnormal expression of CD30, a unique surface biomarker, and the anaplastic lymphoma kinase (ALK gene in lymphoma cells. The nanocomplexes were formulated by incorporating both ALK siRNA and a RNA-based CD30 aptamer probe onto nano-sized polyethyleneimine-citrate carriers. To minimize potential cytotoxicity, the individual components of the nanocomplexes were used at sub-cytotoxic concentrations. Dynamic light scattering showed that formed nanocomplexes were ~140 nm in diameter and remained stable for more than 24 hours in culture medium. Cell binding assays revealed that CD30 aptamer probes selectively targeted nanocomplexes to ALCL cells, and confocal fluorescence microscopy confirmed intracellular delivery of the nanocomplex. Cell transfection analysis showed that nanocomplexes silenced genes in an ALCL cell type-selective fashion. Moreover, exposure of ALCL cells to nanocomplexes carrying both ALK siRNAs and CD30 RNA aptamers specifically silenced ALK gene expression, leading to growth arrest and apoptosis. Conclusions Taken together, our findings indicate that this functional RNA nanocomplex is both tumor cell type-selective and cancer gene-specific for ALCL cells.

  15. Toward immunotherapy with redirected T cells in a large animal model: ex vivo activation, expansion, and genetic modification of canine T cells.

    Science.gov (United States)

    Mata, Melinda; Vera, Juan F; Gerken, Claudia; Rooney, Cliona M; Miller, Tasha; Pfent, Catherine; Wang, Lisa L; Wilson-Robles, Heather M; Gottschalk, Stephen

    2014-10-01

    Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising antitumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells, we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinical studies in dogs within 2 weeks of ex vivo culture. To evaluate the functionality of CAR-expressing canine T cells, we targeted HER2(+) OS. We demonstrate that canine OS is positive for HER2, and that canine T cells expressing a HER2-specific CAR with human-derived transmembrane and CD28.ζ signaling domains recognize and kill HER2(+) canine OS cell lines in an antigen-dependent manner. To reduce the potential immunogenicity of the CAR, we evaluated a CAR with canine-derived transmembrane and signaling domains, and found no functional difference between human and canine CARs. Hence, we have successfully developed a strategy to generate CAR-expressing canine T cells for future preclinical studies in dogs. Testing T-cell therapies in an immunocompetent, outbred animal model may improve our ability to predict their safety and efficacy before conducting studies in humans.

  16. NICOTINAMIDE IN COMPLEX TREATMENT OF LARGE-PLAQUE PARAPSORIASIS AND EARLY STAGES OF MALIGNANT T-CELL SKIN LYMPHOMAS

    Directory of Open Access Journals (Sweden)

    I. V. Khamaganova

    2014-01-01

    Full Text Available Aim: To assess clinical efficacy of nicotinamide in 2 the treatment of patients with early stages of malignant T-cell skin lymphomas and large-plaque parapsoriasis. Materials and methods: 12 patients with erythematous stage of mycosis fungoides and 14 patients with large-plaque parapsoriasis were treated by nicotinamide 15 mg twice daily during 2 weeks. Treatment cycles were repeated 4–5 times per year; topical therapy was also administrated. Results: Nicotinamide demonstrated high therapeutic effect and good tolerability in patients with early stage of mycosis fungoides and large-plaque parapsoriasis. Stable remission was achieved in 1  woman with malignant T-cell lymphoma and 12  patients with large-plaque parapsoriasis; significant clinical improvement was shown in 8 and 12 patients, respectively. Conclusion: Thus, nicotinamide is recommended for comprehensive treatment of large-plaque parapsoriasis and early stages of mycosis fungoides.

  17. Sequencing, analyzing, and modeling small samples from large T cell repertoires

    NARCIS (Netherlands)

    Gerritsen, Bram

    2018-01-01

    Characterizing T cell repertoires is challenging, because repertoires are much larger (i.e. more diverse) than the samples that are sequenced. Additionally, TCRs may differ from each other by as little as a single nucleotide, making it difficult to distinguish erroneous sequences from genuine TCRs.

  18. Large-scale prospective T cell function assays in shipped, unfrozen blood samples

    DEFF Research Database (Denmark)

    Hadley, David; Cheung, Roy K; Becker, Dorothy J

    2014-01-01

    , for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within...... cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities...... North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T...

  19. CXCR5+CD8+T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Tang, Jiahong; Zha, Jie; Guo, Xutao; Shi, Pengcheng; Xu, Bing

    2017-09-01

    Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non-Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8 + T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5 + CD8 + T cell is a novel cell subtype and share CXCR5 expression with CD19 + tumor cells. In this study, we investigated the frequency and function of existing CXCR5 + CD8 + T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5 + CD8 + T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CD8 + T cells as effector (E) cells and autologous CD19 + tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5 + CD8 + T cell- and CXCR5 - CD8 + T cell-mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5 + CD8 + T cells presented stronger cytotoxicity than CXCR5 - CD8 + T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5 + CD8 + T cells than in CXCR5 - CD8 + T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/IL-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5 + CD8 + T cells were significantly elevated. Together, these results suggest that CXCR5 + CD8 + T cells are potential candidates of CD8 + T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression. Copyright © 2017. Published by Elsevier B.V.

  20. Primary and Secondary T-cell Lymphomas of the Breast: Clinico-pathologic Features of 11 Cases

    Science.gov (United States)

    Gualco, Gabriela; Chioato, Lucimara; Harrington, William J.; Weiss, Lawrence M.; Bacchi, Carlos E.

    2009-01-01

    Breast involvement by non-Hodgkin lymphomas is rare, and exceptional for T-cell lymphomas; we studied the morphologic, immunophenotypic, and clinical features of 11 patients with T-cell non-Hodgkin lymphomas involving the breast. Four cases fulfilled the definition criteria for primary breast lymphomas, 3 females and 1 male, with a median age of 51 years. One primary breast lymphomas was T-cell lymphoma unspecified, other was subcutaneous panniculitis-like T-cell lymphoma, and 2 cases were anaplastic large cell lymphomas. One of the anaplastic large cell lymphoma cases was found surrounding a silicone breast implant and presented as clinically as mastitis; whereas the other case occurred in a man. T-cell lymphoma secondarily involved the breast in 7 patients, all women and 1 bilateral, with a median age of 29 years. These secondary breast lymphomas occurred as part of widespread nodal or leukemic disease. Three patients had adult T-cell leukemia/lymphoma, including the patient with bilateral lesions, 3 others had precursor T-lymphoblastic lymphoma/leukemia, and the other presented with a peripheral-T-cell lymphoma nonotherwise specified type. Breast T-cell lymphomas are very infrequent and are morphologically and clinically heterogeneous. PMID:19318917

  1. The non-specific symptoms of breast implant-associated anaplastic large cell lymphoma resulting in delayed diagnosis: A case-based review

    Directory of Open Access Journals (Sweden)

    Reem Dina Jarjis

    2015-12-01

    Full Text Available Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL is a rare entity that has become known as a distinct clinical condition recently. In general, BIA-ALCL patients with a history of breast implants present with non-specific implant-related complications, resulting in delayed diagnosis and appropriate treatment because of the lack of awareness of BIA-ALCL. The cause and pathogenesis have still not been identified, and there are no evidence-based guidelines on how this condition should be detected, treated or followed up because of the rarity of available data. We present the first published Danish case of anaplastic lymphoma kinase negative BIA-ALCL, and review the current literature to raise awareness of and discuss management options for this rare clinical entity.

  2. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation

    International Nuclear Information System (INIS)

    Andersson, E I; Rajala, H L M; Eldfors, S; Ellonen, P; Olson, T; Jerez, A; Clemente, M J; Kallioniemi, O; Porkka, K; Heckman, C; Loughran, T P Jr; Maciejewski, J P; Mustjoki, S

    2013-01-01

    T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene

  3. Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow-Up of 60 Patients

    Science.gov (United States)

    Miranda, Roberto N.; Aladily, Tariq N.; Prince, H. Miles; Kanagal-Shamanna, Rashmi; de Jong, Daphne; Fayad, Luis E.; Amin, Mitual B.; Haideri, Nisreen; Bhagat, Govind; Brooks, Glen S.; Shifrin, David A.; O'Malley, Dennis P.; Cheah, Chan Y.; Bacchi, Carlos E.; Gualco, Gabriela; Li, Shiyong; Keech, John A.; Hochberg, Ephram P.; Carty, Matthew J.; Hanson, Summer E.; Mustafa, Eid; Sanchez, Steven; Manning, John T.; Xu-Monette, Zijun Y.; Miranda, Alonso R.; Fox, Patricia; Bassett, Roland L.; Castillo, Jorge J.; Beltran, Brady E.; de Boer, Jan Paul; Chakhachiro, Zaher; Ye, Dongjiu; Clark, Douglas; Young, Ken H.; Medeiros, L. Jeffrey

    2014-01-01

    Purpose Breast implant–associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown. Patients and Methods We reviewed the literature for all published cases of breast implant–associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up. Results The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively). Conclusion Most patients with breast implant–associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants. PMID:24323027

  4. Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients.

    Science.gov (United States)

    Miranda, Roberto N; Aladily, Tariq N; Prince, H Miles; Kanagal-Shamanna, Rashmi; de Jong, Daphne; Fayad, Luis E; Amin, Mitual B; Haideri, Nisreen; Bhagat, Govind; Brooks, Glen S; Shifrin, David A; O'Malley, Dennis P; Cheah, Chan Y; Bacchi, Carlos E; Gualco, Gabriela; Li, Shiyong; Keech, John A; Hochberg, Ephram P; Carty, Matthew J; Hanson, Summer E; Mustafa, Eid; Sanchez, Steven; Manning, John T; Xu-Monette, Zijun Y; Miranda, Alonso R; Fox, Patricia; Bassett, Roland L; Castillo, Jorge J; Beltran, Brady E; de Boer, Jan Paul; Chakhachiro, Zaher; Ye, Dongjiu; Clark, Douglas; Young, Ken H; Medeiros, L Jeffrey

    2014-01-10

    Breast implant-associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown. We reviewed the literature for all published cases of breast implant-associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up. The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively). Most patients with breast implant-associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.

  5. Anaplastic thyroid cancer

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/000352.htm Anaplastic thyroid cancer To use the sharing features on this page, ... carcinoma is a rare and aggressive form of cancer of the thyroid gland. Causes Anaplastic thyroid cancer is an invasive ...

  6. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study

    Science.gov (United States)

    Mossé, Yael P; Lim, Megan S; Voss, Stephan D; Wilner, Keith; Ruffner, Katherine; Laliberte, Julie; Rolland, Delphine; Balis, Frank M; Maris, John M; Weigel, Brenda J; Ingle, Ashish M; Ahern, Charlotte; Adamson, Peter C; Blaney, Susan M

    2013-01-01

    Summary Background Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. Methods In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials. gov, NCT00939770. Findings 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10

  7. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.

    Science.gov (United States)

    Mossé, Yael P; Lim, Megan S; Voss, Stephan D; Wilner, Keith; Ruffner, Katherine; Laliberte, Julie; Rolland, Delphine; Balis, Frank M; Maris, John M; Weigel, Brenda J; Ingle, Ashish M; Ahern, Charlotte; Adamson, Peter C; Blaney, Susan M

    2013-05-01

    Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770. 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10.1 years (range 1.1-21.4); 43

  8. Peripheral T-cell lymphomas: an evaluation of reproducibility of the updated Kiel classification.

    Science.gov (United States)

    Hastrup, N; Hamilton-Dutoit, S; Ralfkiaer, E; Pallesen, G

    1991-02-01

    Haematoxylin and eosin, and Giemsa stained sections from 100 peripheral T-cell lymphomas were examined blind on two occasions by four experienced haematopathologists in order to evaluate the inter- and intra-observer reproducibility of the updated Kiel classification for these malignancies. In all cases, the T-cell phenotype had been established previously in frozen section using a panel of monoclonal antibodies. Analysis by kappa statistics showed poor reproducibility, both overall and for most subtypes, with the exception of large cell anaplastic lymphoma. The distinction between low- and high-grade lymphomas was also unsatisfactory. These results indicate the need for improved precision in the definition of histological categories of peripheral T-cell lymphoma. The reproducibility of the update Kiel classification for peripheral T-cell lymphomas in its present form is inadequate.

  9. CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma.

    Science.gov (United States)

    Zhou, Yong; Zha, Jie; Lin, Zhijuan; Fang, Zhihong; Zeng, Hanyan; Zhao, Jintao; Luo, Yiming; Li, Zhifeng; Xu, Bing

    2018-01-15

    Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4 + T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19 + cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19 + cells than patients who did not show recurrence. Examining cytotoxic CD4 + T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4 + T cells. Also, frequency of cytotoxic CD4 + T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4 + T cells against autologous CD19 + cells was investigated. We found that the cytotoxic potential of CD4 + T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19 + cells presented a significant reduction after longer incubation with cytotoxic CD4 + T cells, suggesting that cytotoxic CD4 + T cells preferentially eliminated MHC II-expressing CD19 + cells. Blocking MHC II on CD19 + cells significantly reduced the cytolytic capacity of CD4 + T cells. Despite these discoveries, the frequency of cytotoxic CD4 + T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4 + T cells presented an MHC II-dependent cytotoxic potential against autologous CD19 + cells and could potentially represent a future treatment option for DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Occurrence of anaplastic large cell lymphoma following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma.

    Science.gov (United States)

    Ishida, Mitsuaki; Hodohara, Keiko; Yoshida, Keiko; Kagotani, Akiko; Iwai, Muneo; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Nakanishi, Ryota; Harada, Ayumi; Yoshida, Takashi; Okabe, Hidetoshi

    2013-01-01

    IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.

  11. T Cell Histiocyte Rich Large B Cell Lymphoma Presenting as Hemophagocytic Lymphohistiocytosis: An Uncommon Presentation of a Rare Disease

    Directory of Open Access Journals (Sweden)

    Uroosa Ibrahim

    2017-01-01

    Full Text Available T cell histiocyte rich large B cell lymphoma (THRLBCL is a rare subtype of non-Hodgkin’s lymphoma characterized by malignant B cells with reactive T lymphocytes. The pathophysiology is thought to involve cytokine-mediated evasion of T cell immune response by malignant B cells. It usually presents at an advanced stage with extranodal involvement. An extremely unusual manifestation of the disease is hemophagocytic lymphohistiocytosis (HLH which is a hyperinflammatory disorder. We present a case of a 43-year-old male who presented with recurrent fever and recent radiologic imaging showing splenomegaly and right inguinal lymphadenopathy. On presentation, he had a fever of 105°F. Laboratory work-up was consistent with pancytopenia, elevated lactate dehydrogenase, elevated D-dimer, and a ferritin of 24,247 ng/mL. The patient was started on steroid therapy. An excisional biopsy of the right inguinal lymph node was consistent with a diagnosis of THRLBCL and the patient subsequently received six cycles of chemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone after which a PET-CT scan showed no evidence of biologically active disease and ferritin was down to 822 ng/mL. We discuss the clinical manifestations and diagnostic and therapeutic considerations of this rare disease along with a review of reported cases in the literature.

  12. Clinicopathologic, Immunophenotypic, Cytogenetic, and Molecular Features of γδ T-Cell Large Granular Lymphocytic Leukemia: An Analysis of 14 Patients Suggests Biologic Differences With αβ T-Cell Large Granular Lymphocytic Leukemia. [corrected].

    Science.gov (United States)

    Yabe, Mariko; Medeiros, L Jeffrey; Wang, Sa A; Konoplev, Sergej; Ok, Chi Young; Loghavi, Sanam; Lu, Gary; Flores, Lauren; Khoury, Joseph D; Cason, R Craig; Young, Ken H; Miranda, Roberto N

    2015-10-01

    T-cell large granular lymphocytic (T-LGL) leukemia is a rare disorder in which the neoplastic cells usually express the αβ T-cell receptor (TCR). To determine the significance of γδ TCR expression in this leukemia, we compared the clinicopathologic, immunophenotypic, and genetic features of patients with T-LGL leukemia expressing γδ TCR or αβ TCR. We used the World Health Organization classification criteria to confirm the diagnosis. All patients were diagnosed and treated at our institution. We identified 14 patients with γδ T-LGL leukemia, 11 men and three women; six (43%) patients had a history of rheumatoid arthritis, 10 (71%) had neutropenia, four (29%) had thrombocytopenia, and three (21%) had anemia. Eight (67%) of 12 patients had a CD4-/CD8- phenotype, and four (33%) had a CD4-/CD8+ phenotype. The median overall survival was 62 months. Patients with γδ T-LGL leukemia were more likely to have rheumatoid arthritis (P = .04), lower absolute neutrophil count (P = .04), lower platelet count (P = .004), and a higher frequency of the CD4-/CD8- phenotype (P < .0001). However, there was no significant difference in overall survival between the two groups (P = .64). Although patients with γδ and αβ T-LGL leukemia show some different clinical or phenotypic features, overall survival is similar, suggesting that γδ TCR expression does not carry prognostic significance. Copyright© by the American Society for Clinical Pathology.

  13. Large-scale Isolation of Highly Pure "Untouched" Regulatory T Cells in a GMP Environment for Adoptive Cell Therapy.

    Science.gov (United States)

    Haase, Doreen; Puan, Kia Joo; Starke, Mireille; Lai, Tuck Siong; Soh, Melissa Yan Ling; Karunanithi, Iyswariya; San Luis, Boris; Poh, Tuang Yeow; Yusof, Nurhashikin; Yeap, Chun Hsien; Phang, Chew Yen; Chye, Willis Soon Yuan; Chan, Marieta; Koh, Mickey Boon Chai; Goh, Yeow Tee; Bertin-Maghit, Sebastien; Nardin, Alessandra; Ho, Liam Pock; Rotzschke, Olaf

    2015-01-01

    Adoptive cell therapy is an emerging treatment strategy for a number of serious diseases. Regulatory T (Treg) cells represent 1 cell type of particular interest for therapy of inflammatory conditions, as they are responsible for controlling unwanted immune responses. Initial clinical trials of adoptive transfer of Treg cells in patients with graft-versus-host disease were shown to be safe. However, obtaining sufficient numbers of highly pure and functional Treg cells with minimal contamination remains a challenge. We developed a novel approach to isolate "untouched" human Treg cells from healthy donors on the basis of negative selection using the surface markers CD49d and CD127. This procedure, which uses an antibody cocktail and magnetic beads for separation in an automated system (RoboSep), was scaled up and adapted to be compatible with good manufacturing practice conditions. With this setup we performed 9 Treg isolations from large-scale leukapheresis samples in a good manufacturing practice facility. These runs yielded sufficient numbers of "untouched" Treg cells for immediate use in clinical applications. The cell preparations consisted of viable highly pure FoxP3-positive Treg cells that were functional in suppressing the proliferation of effector T cells. Contamination with CD4 effector T cells was cell types did not exceed 2% in the final product. Remaining isolation reagents were reduced to levels that are considered safe. Treg cells isolated with this procedure will be used in a phase I clinical trial of adoptive transfer into leukemia patients developing graft-versus-host disease after stem cell transplantation.

  14. Large-scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA barcodes

    DEFF Research Database (Denmark)

    Bentzen, Amalie Kai; Marquard, Andrea Marion; Lyngaa, Rikke Birgitte

    2016-01-01

    Identification of the peptides recognized by individual T cells is important for understanding and treating immune-related diseases. Current cytometry-based approaches are limited to the simultaneous screening of 10-100 distinct T-cell specificities in one sample. Here we use peptide-major histoc...

  15. Course and Clinical Significance of CD8+ T-Cell Counts in a Large Cohort of HIV-Infected Individuals

    DEFF Research Database (Denmark)

    Helleberg, Marie; Kronborg, Gitte; Ullum, Henrik

    2015-01-01

    OBJECTIVES: To examine trajectories of CD8(+) T-cell counts before and after combination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-infected individuals and associations with mortality. METHODS: CD8(+) T-cell counts were measured in 3882 HIV-infected individuals who...... received care in Copenhagen during 1995-2012. Reference values were obtained from 1230 persons from the background population. Mortality rate ratios were estimated by Poisson regression. RESULTS: CD8(+) T-cell counts were elevated during untreated HIV infection and remained elevated through 10 years of c......ART. A slight drop of 130 cells/µL (interquartile range, -160 to 410 cells/μL) in the median CD8(+) T-cell count was observed after cART initiation. CD8(+) T-cell counts stabilized at approximately 900 cells/µL (95th percentile of the background population, 835 cells/µL). Markedly elevated CD8(+) T-cell counts...

  16. SOLITARY T-CELL HEPATIC LYMPHOMA WITH LARGE GRANULAR LYMPHOCYTE MORPHOLOGY IN A CAPTIVE CHEETAH (ACINONYX JUBATUS).

    Science.gov (United States)

    Lindemann, Dana M; Carpenter, James W; Almes, Kelli M; Schumacher, Loni; Ryseff, Julia K; Hallman, Mackenzie

    2015-06-01

    A 13-yr-old male cheetah (Acinonyx jubatus) presented for an acute history of lateral recumbency and anorexia. Upon physical examination under general anesthesia, severe icterus was noted. A serum biochemical profile confirmed markedly elevated total bilirubin and alanine transaminase. Based on ultrasound-guided liver aspirates and cytology, a presumptive diagnosis of large granular lymphocyte hepatic lymphoma was reached. Abdominal and thoracic radiographs did not assist in reaching an antemortem diagnosis. Postmortem examination and histopathology provided a definitive diagnosis of hepatic lymphoma with acute massive hepatocelluar necrosis and hemorrhage, as well as concurrent lesions of gastric ulcers, ulcerative and sclerosing enteritis, myocardial hypertrophy, and splenic myelolipomas. Immunohistochemistry of the liver yielded CD-3 positive and CD-20 negative results, confirming lymphocytes of a T-cell lineage. Due to concern for possible retrovirus-associated disease, enzyme-linked immunosorbent assays for feline leukemia virus and feline immunodeficiency virus were performed retrospectively on a banked serum sample and yielded negative results, thus diminishing concern for the male conspecific housed in the same exhibit.

  17. The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression.

    Science.gov (United States)

    Georgakis, Georgios V; Li, Yang; Rassidakis, Georgios Z; Medeiros, L Jeffrey; Younes, Anas

    2006-12-01

    Heat shock protein 90 (HSP90) chaperones and maintains the molecular integrity of a variety of signal transduction proteins, including the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein, a genetic abnormality that is frequently observed in anaplastic large cell lymphoma (ALCL) cells. Here we demonstrate that HSP90 is overexpressed in primary and cultured ALK-positive and ALK-negative ALCL cells, and we evaluate the potential role of the small molecule inhibitor of HSP90, 17-allylamino-17-demethoxygeldanamycin (17-AAG) in treating ALCL. The antiproliferative effect of 17-AAG-cultured cells was determined by MTS assay. Apoptosis and cell-cycle arrest were determined by Annexin-V/propidium iodide and propidium iodide staining, respectively, and fluorescein-activated cell sorting analysis. Expression of HSP90 was evaluated by immunohistochemistry, and molecular changes were determined by Western blot. Treatment of cultured ALCL cells with 17-AAG induced cell-cycle arrest and apoptosis, irrespective of ALK expression. At the molecular level, 17-AAG induced degradation of ALK and Akt proteins, dephosphorylated extracellular signal-regulated kinase, and degraded the cell-cycle regulatory protein cyclin D1 and its cyclin-dependent kinases, CDK4 and CDK6, but had a differential effect on p27 and p53 proteins. Inhibition of extracellular signal-regulated kinase phosphorylation by the mitogen activated protein kinase inhibitor U0126 induced cell death in all ALCL cell lines, and sublethal concentration 17-AAG showed synergistic antiproliferative effects when combined with U0126 or doxorubicin. Our data demonstrate that targeting HSP90 function by 17-AAG may offer a novel therapeutic strategy for ALCL, either as single-agent activity or by combining 17-AAG with conventional or targeted therapeutic schemes.

  18. Large-scale prospective T cell function assays in shipped, unfrozen blood samples: experiences from the multicenter TRIGR trial.

    Science.gov (United States)

    Hadley, David; Cheung, Roy K; Becker, Dorothy J; Girgis, Rose; Palmer, Jerry P; Cuthbertson, David; Krischer, Jeffrey P; Dosch, Hans-Michael

    2014-02-01

    Broad consensus assigns T lymphocytes fundamental roles in inflammatory, infectious, and autoimmune diseases. However, clinical investigations have lacked fully characterized and validated procedures, equivalent to those of widely practiced biochemical tests with established clinical roles, for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities of the samples and the unstimulated cell counts in the viable samples. Also, subject age was significantly associated with the number of unstimulated cells and T cell proliferation to positive activators. Finally, we observed a pattern of statistically significant increases in T cell responses to tetanus toxin around the timing of infant vaccinations. This assay platform and shipping protocol satisfy the criteria for robust and reproducible long-term measurements of human T cell function, comparable to those of established blood biochemical tests. We present a stable technology for prospective disease-relevant T cell analysis in immunological diseases, vaccination medicine, and measurement of herd immunity.

  19. T-cell prolymphocytic leukemia in a 63-year-old female with a pre-existing T-cell large granular lymphocytic leukemia: metachronous T-cell leukemias with discordant subset restrictions (CD4 versus CD8) and distinct clonal identities.

    Science.gov (United States)

    Wei, Qiang; Papavassiliou, Paulie; Rehder, Catherine; Sebastian, Siby; Wang, Endi

    2014-12-01

    A 55-year-old female with T-cell large granular lymphocytic leukemia (T-LGL) (CD8+) was initially treated with anti-thymocyte globulin and then cyclosporine due to anemia/neutropenia. While the severity of cytopenia varied with the therapy, the T-LGL persisted. Eight years after the initial diagnosis, she developed lymphadenopathy and hepatosplenomegaly. A complete blood cell count revealed leukocytosis, anemia and thrombocytopenia with ∼ 80% lymphocytes. In contrast to the LGL cells, the blood lymphocytes at this time were medium-large in size and had oval/irregular nuclei, condensed chromatin, indistinct nucleoli and a moderate amount of basophilic cytoplasm, many with elongated vacuoles, and some with cytoplasmic projections. The abnormal lymphocytes comprised ∼ 30% of the bone marrow cellularity with interstitial infiltrates/aggregates. Immunophenotypic analyses demonstrated a T-cell neoplasm with features suggestive of T-cell prolymphocytic leukemia (T-PLL) (CD4+). Cytogenetic analysis revealed a novel clone with complex abnormalities. PCR-based TRG gene rearrangement studies detected a clonal amplicon distinct from that of the preexisting T-LGL. Because of the chronological sequence of the two T-cell neoplasms, this case was initially considered an aggressive transformation of T-LGL. However, this was ultimately excluded by a discordant CD4-subset restriction and the presence of a distinct clonal identity. While these two T-cell neoplasms may have intrinsic connections, the underlying pathogenesis remains to be investigated. Copyright © 2014 Elsevier GmbH. All rights reserved.

  20. Eradication of large solid tumors by gene therapy with a T cell receptor targeting a single cancer-specific point mutation

    Science.gov (United States)

    Leisegang, Matthias; Engels, Boris; Schreiber, Karin; Yew, Poh Yin; Kiyotani, Kazuma; Idel, Christian; Arina, Ainhoa; Duraiswamy, Jaikumar; Weichselbaum, Ralph R.; Uckert, Wolfgang; Nakamura, Yusuke; Schreiber, Hans

    2015-01-01

    Purpose Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic non-synonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T cell receptor (TCR) that is specific for a single AAS. Experimental Design By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. Results When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intra-tumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. Conclusions Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. PMID:26667491

  1. Circulating CXCR5+CD4+ T cells assist in the survival and growth of primary diffuse large B cell lymphoma cells through interleukin 10 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Zhanshan [Department of Transfusion, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Qian, Guangfang [Department of Endocrinology, Zhangqiu Municipal Hospital of Traditional Chinese Medicine, Zhangqiu, Shandong 250200 (China); Zang, Yan; Gu, Haihui; Huang, Yanyan; Zhu, Lishuang; Li, Jinqi; Liu, Yang; Tu, Xiaohua [Department of Transfusion, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Song, Haihan [Emergency Center, East Hospital, Shanghai 200120 (China); Qian, Baohua, E-mail: qianbhl963@163.com [Department of Transfusion, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China)

    2017-01-01

    Diffuse large B cell lymphoma (DLBCL) is a common and aggressive cancer caused by the malignant transformation of B cells. Although it has been established that the follicular helper T (Tfh) cells play a central role in B cell development, little information is available on their involvement in DLBCL pathogenesis. We studied the role of the peripheral Tfh equivalent, the CXCR5{sup +} CD4{sup +} T cells, in DLBCL. Data showed that compared to CXCR5{sup -} CD4{sup +} T cells, CXCR5{sup +} CD4{sup +} T cells were significantly more effective at promoting the proliferation as well as inhibiting the apoptosis of primary autologous DLBCL tumor cells. Surprisingly, we found that at equal cell numbers, CXCR5{sup +} CD4{sup +} T cells in DLBCL patients secreted significantly less interleukin (IL)-21 than CXCR5{sup -} CD4{sup +} T cells, while the level of IL-10 secretion was significant elevated in the CXCR5{sup +} compartment compared to the CXCR5{sup -} compartment. Neutralization of IL-10 in the primary DLBCL-CXCR5{sup +} CD4{sup +} T cell coculture compromised the CXCR5{sup +} CD4{sup +} T cell-mediated pro-tumor effects, in a manner that was dependent on the concentration of anti-IL-10 antibodies. The CXCR5{sup +} compartment also contained significantly lower frequencies of cytotoxic CD4{sup +} T cells than the CXCR5{sup -} compartment. In conclusion, our investigations discovered a previously unknown pro-tumor role of CXCR5-expressing circulating CD4{sup +} T cells, which assisted the survival and proliferation of primary DLBCL cells through IL-10. - Highlights: • We studied the role of the peripheral Tfh in DLBCL. • Tfh were effective at promoting the proliferation of primary DLBCL tumor cells. • Tfh were effective at inhibiting the apoptosis of primary DLBCL tumor cells. • IL-10 secretion in Tfh was significant elevated in DLBCL. • Neutralization of IL-10 compromised Tfh-mediated pro-tumor effects.

  2. Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes.

    Science.gov (United States)

    Clemente, Michael J; Przychodzen, Bartlomiej; Jerez, Andres; Dienes, Brittney E; Afable, Manuel G; Husseinzadeh, Holleh; Rajala, Hanna L M; Wlodarski, Marcin W; Mustjoki, Satu; Maciejewski, Jaroslaw P

    2013-12-12

    New massively parallel sequencing technology enables, through deep sequencing of rearranged T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) regions, a previously inaccessible level of TCR repertoire analysis. The CDR3 repertoire diversity reflects clonal composition, the potential antigenic recognition spectrum, and the quantity of available T-cell responses. In this context, T-large granular lymphocyte (T-LGL) leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with autoimmune diseases and various cytopenias. Using CD8(+) T-LGL leukemia as a model disease, we set out to evaluate and compare the TCR deep-sequencing spectra of both patients and healthy controls to better understand how TCR deep sequencing could be used in the diagnosis and monitoring of not only T-LGL leukemia but also reactive processes such as autoimmune disease and infection. Our data demonstrate, with high resolution, significantly decreased diversity of the T-cell repertoire in CD8(+) T-LGL leukemia and suggest that many T-LGL clonotypes may be private to the disease and may not be present in the general public, even at the basal level.

  3. Anaplastic lymphoma kinase-positive large B-cell lymphoma: Clinico-pathological study of 17 cases with review of literature.

    Directory of Open Access Journals (Sweden)

    Xiang-Nan Jiang

    Full Text Available We retrospectively analysed 17 cases of anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+, LBCL according to the morphological, immunohistochemical, molecular and clinical features, using which we intend to elucidate the clinicopathological characteristics of this rare entity. In this study, all cases de facto share common features that defined them as a single entity, and various characteristics may expand the spectrum. Among 15 cases, 60% followed an aggressive clinical course with advanced stage and high IPI scores; the median survival of these patients was only 8 months. An analysis showed that both the IPI score and the Ann Arbor stage were significant prognostic factors. Most patients received a chemotherapy regimen including CHOP, CHOEP, EPOCH, and CVAD, and some also underwent localized radiotherapy. However, ALK+, LBCL cases display a dismal clinical outcome and can only be cured with conventional chemotherapy protocols at the stage of localized disease. Novel front-line intensive chemotherapy regimens should therefore be evaluated in this group of patients.

  4. Intravesicular taxane-induced dermatotoxicity in a 78-year-old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma.

    Science.gov (United States)

    Pelletier, Daniel; O'Donnell, Michael; Stone, Mary Seabury; Liu, Vincent

    2018-02-27

    Patients treated with intravesical bacillus Calmette-Guerin therapy for urothelial carcinoma often become refractory and experience recurrent disease, thus necessitating alternative intravesical treatment modalities if the patient is to be spared the morbidities associated with radical cystectomy. Intravesical treatment with taxane-based chemotherapy, such as docetaxel, has gained traction in urologic oncology, proving to be an effective salvage therapy in such patients. Systemic taxane-based chemotherapeutic regimens have long been used in several advanced malignancies, and their systemic side effects and associated histologic correlates have been extensively documented. In contrast to adverse effects associated with systemic administration, intravesical taxane administration has thus far proven to be well-tolerated, with little to no systemic absorption. To our knowledge, features of taxane-induced systemic effects have not been reported in this setting. Herein, we report a case of a patient with recurrent urothelial carcinoma treated with intravesical docetaxel, along with primary cutaneous anaplastic large cell lymphoma, who developed characteristic dermatotoxic histologic findings associated with intravenous taxane administration. As such histopathologic findings often represent close mimickers of neoplastic and infectious etiologies, knowledge of the potential for systemic manifestations of taxane therapy in patients treated topically may prevent potentially costly diagnostic pitfalls. This article is protected by copyright. All rights reserved.

  5. Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex12

    Science.gov (United States)

    Piazza, Rocco; Magistroni, Vera; Mogavero, Angela; Andreoni, Federica; Ambrogio, Chiara; Chiarle, Roberto; Mologni, Luca; Bachmann, Petra S; Lock, Richard B; Collini, Paola; Pelosi, Giuseppe; Gambacorti-Passerini, Carlo

    2013-01-01

    BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation. PMID:23633923

  6. Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex

    Directory of Open Access Journals (Sweden)

    Rocco Piazza

    2013-05-01

    Full Text Available BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2 corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.

  7. Lack of common TCRA and TCRB clonotypes in CD8+/ TCRαβ+ T-cell large granular lymphocyte leukemia: A review on the role of antigenic selection in the immunopathogenesis of CD8+ T-LGL

    NARCIS (Netherlands)

    Y. Sandberg (Yorick); M.J. Kallemeijn (Martine); W.A. Dik (Willem); D. Tielemans; I.L.M. Wolvers-Tettero (I. L M); E.J. van Gastel-Mol (Ellen); T. Szczepanski (Tomasz); Y. Pol (Y.); N. Darzentas (Nikos); J.J.M. van Dongen (Jacques); A.W. Langerak (Anton)

    2014-01-01

    textabstractClonal CD8 +/T-cell receptor (TCR)αβ+ T-cell large granular lymphocyte (T-LGL) proliferations constitute the most common subtype of T-LGL leukemia. Although the etiology of T-LGL leukemia is largely unknown, it has been hypothesized that chronic antigenic stimulation contributes to the

  8. Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation.

    Science.gov (United States)

    Kiss, Izabella; Unger, Christine; Huu, Chi Nguyen; Atanasov, Atanas Georgiev; Kramer, Nina; Chatruphonprasert, Waranya; Brenner, Stefan; McKinnon, Ruxandra; Peschel, Andrea; Vasas, Andrea; Lajter, Ildiko; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R; Diaz, Rene; Frisch, Richard; Dirsch, Verena M; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N; Passreiter, Claus M; Peter-Vörösmarty, Barbara; Mader, Robert M; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupko, Istvan; Hohmann, Judit; Krupitza, Georg

    2015-01-28

    An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this

  9. PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

    Directory of Open Access Journals (Sweden)

    Esperanza Martín-Sánchez

    Full Text Available Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL. The Proviral Integration site of Moloney murine leukemia virus (PIM kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs and pharmacologically (mainly with the pan-PIM inhibitor (PIMi ETP-39010 in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

  10. CD30 Is Dispensable for T-Cell Responses to Influenza Virus and Lymphocytic Choriomeningitis Virus Clone 13 but Contributes to Age-Associated T-Cell Expansion in Mice

    Directory of Open Access Journals (Sweden)

    Angela C. Zhou

    2017-09-01

    Full Text Available CD30 is a tumor necrosis factor receptor (TNFR family member whose expression is associated with Hodgkin’s disease, anaplastic large cell lymphomas, and other T and B lymphoproliferative disorders in humans. A limited number of studies have assessed the physiological role of CD30/CD30 ligand interactions in control of infection in mice. Here, we assess the role of CD30 in T-cell immunity to acute influenza and chronic lymphocytic choriomeningitis virus (LCMV clone 13 infection, two viral infections in which other members of the TNFR superfamily are important for T-cell responses. We show that CD30 is expressed on activated but not resting CD4 and CD8 T cells in vitro, as well as on regulatory T cells and marginally on T helper 1 cells in vivo during influenza infection. Despite this, CD4 and CD8 T-cell expansion in response to influenza virus was comparable in CD30+/+ and CD30−/− littermates, with no discernable role for the pathway in the outcome of influenza infection. Similarly, during persistent infection with LCMV clone 13, CD30 plays no obvious role in CD4 or CD8 T-cell responses, the level of T-cell exhaustion or viral control. In contrast, in the steady state, we observed increased numbers of total CD4 and CD8 T cells as well as increased numbers of regulatory T cells in unimmunized older (~8 months CD30+/+ but not in CD30−/− age-matched littermates. Naive T-cell numbers were unchanged in the aged CD30+/+ mice compared to their CD30−/− littermate controls, rather the T-cell expansions were explained by an increase in CD4+ and CD8+ CD44mid-hiCD62L− effector memory cells, with a similar trend in the central memory T-cell compartment. In contrast, CD30 did not impact the numbers of T cells in young mice. These data suggest a role for CD30 in the homeostatic regulation of T cells during aging, contributing to memory T-cell expansions, which may have relevance for CD30 expression in human T-cell lymphoproliferative diseases.

  11. NKT Cell-TCR Expression Activates Conventional T Cells in Vivo, but Is Largely Dispensable for Mature NKT Cell Biology

    Science.gov (United States)

    Vahl, J. Christoph; Heger, Klaus; Knies, Nathalie; Hein, Marco Y.; Boon, Louis; Yagita, Hideo; Polic, Bojan; Schmidt-Supprian, Marc

    2013-01-01

    Natural killer T (NKT) cell development depends on recognition of self-glycolipids via their semi-invariant Vα14i-TCR. However, to what extent TCR-mediated signals determine identity and function of mature NKT cells remains incompletely understood. To address this issue, we developed a mouse strain allowing conditional Vα14i-TCR expression from within the endogenous Tcrα locus. We demonstrate that naïve T cells are activated upon replacement of their endogenous TCR repertoire with Vα14i-restricted TCRs, but they do not differentiate into NKT cells. On the other hand, induced TCR ablation on mature NKT cells did not affect their lineage identity, homeostasis, or innate rapid cytokine secretion abilities. We therefore propose that peripheral NKT cells become unresponsive to and thus are independent of their autoreactive TCR. PMID:23853545

  12. NKT cell-TCR expression activates conventional T cells in vivo, but is largely dispensable for mature NKT cell biology.

    Directory of Open Access Journals (Sweden)

    J Christoph Vahl

    Full Text Available Natural killer T (NKT cell development depends on recognition of self-glycolipids via their semi-invariant Vα14i-TCR. However, to what extent TCR-mediated signals determine identity and function of mature NKT cells remains incompletely understood. To address this issue, we developed a mouse strain allowing conditional Vα14i-TCR expression from within the endogenous Tcrα locus. We demonstrate that naïve T cells are activated upon replacement of their endogenous TCR repertoire with Vα14i-restricted TCRs, but they do not differentiate into NKT cells. On the other hand, induced TCR ablation on mature NKT cells did not affect their lineage identity, homeostasis, or innate rapid cytokine secretion abilities. We therefore propose that peripheral NKT cells become unresponsive to and thus are independent of their autoreactive TCR.

  13. Vorinostat, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Lymphoma or Previously Untreated T-Cell Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

    Science.gov (United States)

    2017-04-17

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Waldenström Macroglobulinemia

  14. Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

    Science.gov (United States)

    Charbonneau, Bridget; Moysich, Kirsten B; Kalli, Kimberly R; Oberg, Ann L; Vierkant, Robert A; Fogarty, Zachary C; Block, Matthew S; Maurer, Matthew J; Goergen, Krista M; Fridley, Brooke L; Cunningham, Julie M; Rider, David N; Preston, Claudia; Hartmann, Lynn C; Lawrenson, Kate; Wang, Chen; Tyrer, Jonathan; Song, Honglin; deFazio, Anna; Johnatty, Sharon E; Doherty, Jennifer A; Phelan, Catherine M; Sellers, Thomas A; Ramirez, Starr M; Vitonis, Allison F; Terry, Kathryn L; Van Den Berg, David; Pike, Malcolm C; Wu, Anna H; Berchuck, Andrew; Gentry-Maharaj, Aleksandra; Ramus, Susan J; Diergaarde, Brenda; Shen, Howard; Jensen, Allan; Menkiszak, Janusz; Cybulski, Cezary; Lubiłski, Jan; Ziogas, Argyrios; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Lester, Jenny; Walsh, Christine; Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn; Garcia-Closas, Montserrat; Yang, Hannah; Brinton, Louise A; Spiewankiewicz, Beata; Rzepecka, Iwona K; Dansonka-Mieszkowska, Agnieszka; Seibold, Petra; Rudolph, Anja; Paddock, Lisa E; Orlow, Irene; Lundvall, Lene; Olson, Sara H; Hogdall, Claus K; Schwaab, Ira; du Bois, Andreas; Harter, Philipp; Flanagan, James M; Brown, Robert; Paul, James; Ekici, Arif B; Beckmann, Matthias W; Hein, Alexander; Eccles, Diana; Lurie, Galina; Hays, Laura E; Bean, Yukie T; Pejovic, Tanja; Goodman, Marc T; Campbell, Ian; Fasching, Peter A; Konecny, Gottfried; Kaye, Stanley B; Heitz, Florian; Hogdall, Estrid; Bandera, Elisa V; Chang-Claude, Jenny; Kupryjanczyk, Jolanta; Wentzensen, Nicolas; Lambrechts, Diether; Karlan, Beth Y; Whittemore, Alice S; Culver, Hoda Anton; Gronwald, Jacek; Levine, Douglas A; Kjaer, Susanne K; Menon, Usha; Schildkraut, Joellen M; Pearce, Celeste Leigh; Cramer, Daniel W; Rossing, Mary Anne; Chenevix-Trench, Georgia; Pharoah, Paul D P; Gayther, Simon A; Ness, Roberta B; Odunsi, Kunle; Sucheston, Lara E; Knutson, Keith L; Goode, Ellen L

    2014-04-01

    The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.

  15. Primary Ki-1-positive T-cell lymphoma of the brain--an aggressive subtype of lymphoma: case report and review of the literature.

    Science.gov (United States)

    Goldbrunner, R; Warmuth-Metz, M; Tonn, J C; Vince, G H; Roosen, K

    1996-07-01

    By detection of the Ki-1 antigen, Stein (1985) defined a new entity of anaplastic large cell lymphoma [24]. Apart from our case, only four further cases of Ki-1 positive primary central nervous system lymphoma (PCNSL) have been reported in the literature to date. A 63-year-old man presented with two frontal and parietal mass lesions and one ring lesion on computed tomography scan. Clinically, no evidence of brain metastases or abscesses could be found. Immunohistochemical investigations of biopsy specimens revealed a large cell anaplastic T-cell lymphoma positive to Ki-1 antigen. In spite of all therapeutic efforts, the patient died less than 3 months after the onset of symptoms. In all cases the clinical course was very rapid, suggesting that Ki-1 positive PCNSL might form an aggressive subtype of lymphomas. Since the radiologic appearance was atypical and clinical diagnosis was not possible, diagnostic biopsy for immunohistochemical diagnosis should be performed.

  16. Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

    Science.gov (United States)

    2018-04-10

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Primary Cutaneous B-Cell Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Non-Hodgkin Lymphoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  17. Prognosis of mature T cell lymphoma is poorer than that of diffuse large B cell lymphoma in IPI low-risk group, but not in intermediate- and high-risk groups.

    Science.gov (United States)

    Kihara, Rika; Watanabe, Tomoyuki; Yano, Takahiro; Uike, Naokuni; Okamura, Seiichi; Kawano, Fumio; Hanada, Shuichi; Sunami, Kazutaka; Inoue, Nobumasa; Sawamura, Morio; Yoshida, Shin-Ichiro; Shimomura, Takeshi; Kitano, Kiyoshi; Kojima, Yuki; Horibe, Keizo; Nagai, Hirokazu

    2013-01-01

    Mature T cell lymphoma has been noted for poor prognosis when compared with B cell lymphoma, even in the pre-rituximab era. To confirm this difference, a retrospective cohort study was conducted. One hundred-and nineteen patients with mature T cell lymphoma and 568 patients with diffuse large B cell lymphoma (DLBCL) who did not receive rituximab as first induction were studied. Overall survival (OS) was worse for patients with international prognostic index (IPI) scores indicating low-risk mature T cell lymphoma than for those with DLBCL (3-year OS 87 % vs. 58 %, P = 0.001), but not in other risk groups. Prognosis of mature T cell lymphoma was significantly poorer in the IPI low-risk group, as compared with DLBCL.

  18. A 16-gene signature distinguishes anaplastic astrocytoma from glioblastoma.

    Directory of Open Access Journals (Sweden)

    Soumya Alige Mahabala Rao

    Full Text Available Anaplastic astrocytoma (AA; Grade III and glioblastoma (GBM; Grade IV are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a more robust molecular classifier, we analysed RT-qPCR expression data of 175 differentially regulated genes across astrocytoma using Prediction Analysis of Microarrays (PAM and found the most discriminatory 16-gene expression signature for the classification of anaplastic astrocytoma and glioblastoma. The 16-gene signature obtained in the training set was validated in the test set with diagnostic accuracy of 89%. Additionally, validation of the 16-gene signature in multiple independent cohorts revealed that the signature predicted anaplastic astrocytoma and glioblastoma samples with accuracy rates of 99%, 88%, and 92% in TCGA, GSE1993 and GSE4422 datasets, respectively. The protein-protein interaction network and pathway analysis suggested that the 16-genes of the signature identified epithelial-mesenchymal transition (EMT pathway as the most differentially regulated pathway in glioblastoma compared to anaplastic astrocytoma. In addition to identifying 16 gene classification signature, we also demonstrated that genes involved in epithelial-mesenchymal transition may play an important role in distinguishing glioblastoma from anaplastic astrocytoma.

  19. T-cell count

    Science.gov (United States)

    ... count URL of this page: //medlineplus.gov/ency/article/003516.htm T-cell count To use the sharing features on this ... as hepatitis or mononucleosis Lower than normal T-cell levels may be due to: Acute viral infections Aging Cancer Immune system diseases, such as HIV/AIDS ...

  20. Extensive Growth of an Anaplastic Meningioma

    Directory of Open Access Journals (Sweden)

    Hajrullah Ahmeti

    2013-01-01

    Full Text Available We present the case of a 30-year-old male patient with an almost complete destruction of the calvarial bone through an anaplastic meningioma diagnosed in line with dizziness. Neuroimaging revealed an extensive growing, contrast enhancing lesion expanding at the supra- and infratentorial convexity, infiltrating and destroying large parts of the skull, and infiltrating the skin. Due to progressive ataxia and dysarthria with proven tumor growth in the posterior fossa in the continuing course, parts of the tumor were resected. A surgical procedure with the aim of complete tumor resection in a curative manner was not possible. Six months after the first operation, due to a new tumor progression, most extensive tumor resection was performed. Due to the aggressive and destructive growth with a high rate of recurrence and tendency of metastases, anaplastic meningiomas can be termed as malignant tumors. The extrinsic growth masks the tumor until they reach a size, which makes these tumors almost unresectable. In the best case scenarios, the five-year survival is about 50%. With the presented case, we would like to show the aggressive behavior of anaplastic meningiomas in a very illustrative way. Chemotherapy, radiotherapy, and surgery reach their limits in this tumor entity.

  1. A large fraction of human peripheral blood gamma/delta + T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein

    OpenAIRE

    1990-01-01

    We report that M. tuberculosis organisms, but neither PHA nor allogeneic stimulator cells, preferentially activate gamma/delta+ cells within E rosette-purified peripheral blood T cells. gamma/delta+ T cells from purified protein derivative (PPD)-nonimmune healthy donors were enriched by depletion of CD4+ and CD8+ cells; double-negative (DN) cells contained 65-92% gamma/delta+ T cells. Limiting dilution (LD) analyses revealed that 1 of 2-19 purified DN cells proliferated in response to mycobac...

  2. Computer-driven quantitative image analysis in the assessment of tumor cell and T cell features in diffuse large B cell lymphomas.

    Science.gov (United States)

    Gaudio, Francesco; Tamma, Roberto; Ingravallo, Giuseppe; Perrone, Tommasina; Laddaga, Filomena Emanuela; De Candia, Mariastella; Maiorano, Eugenio; Ribatti, Domenico; Specchia, Giorgina

    2018-04-01

    Diffuse large B cell lymphoma (DLBCL) is recognized as the most common non-Hodgkin lymphoma subtype. Advanced high-resolution digital scans of pathology slides have enabled the development of computer-based image analysis algorithms that may assist pathologists in quantifying immunohistochemical stains. In this retrospective study, we reviewed data from 29 patients affected by DLBCL. In order to evaluate the number of tumor cells and microenvironment T cells, we performed an analysis of CD20, Ki67, and CD3 counts, assessed with the Positive Pixel Count algorithm embedded in the Aperio ImageScope software. A lower tumor cell count was observed in patients with a non-germinal center immunophenotype, high LDH, splenomegaly and an IPI ≥ 3. A lower number of CD3 was observed in patients with bulky disease, an IPI ≥ 3 and disease stage 3-4. Overall, these data confirm that quantitative analysis of the tumor cells and of the tumor microenvironment by means of computer-driven quantitative image analysis may add new information in DLBCL diagnosis.

  3. CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Patients With Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2018-01-25

    B Acute Lymphoblastic Leukemia; CD19 Positive; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma of the Elderly; Minimal Residual Disease; Philadelphia Chromosome Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

  4. T-cell costimulation

    DEFF Research Database (Denmark)

    Owens, T

    1996-01-01

    The CD40L molecule expressed by CD4+ regulatory T lymphocytes is known to deliver signals that activate B cells and macrophages. It now appears that CD40L regulates T cells themselves, during both their development and their participation in adaptive immune responses....

  5. Characterization of patients with aggressive adult T-cell leukemia-lymphoma in Okinawa, Japan: a retrospective analysis of a large cohort.

    Science.gov (United States)

    Nishi, Yukiko; Fukushima, Takuya; Nomura, Shogo; Tomoyose, Takeaki; Nakachi, Sawako; Morichika, Kazuho; Tedokon, Iori; Tamaki, Keita; Shimabukuro, Natsuki; Taira, Naoya; Miyagi, Takashi; Karimata, Kaori; Ohama, Masayo; Yamanoha, Atsushi; Tamaki, Kazumitsu; Hayashi, Masaki; Arakaki, Hitoshi; Uchihara, Jun-Nosuke; Ohshiro, Kazuiku; Asakura, Yoshitaka; Kuba-Miyara, Megumi; Karube, Kennosuke; Masuzaki, Hiroaki

    2016-10-01

    Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis.

  6. Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma.

    Science.gov (United States)

    Pinheiro, Dammy; Chang, Yu-Mei; Bryant, Hannah; Szladovits, Balazs; Dalessandri, Tim; Davison, Lucy J; Yallop, Elizabeth; Mills, Emily; Leo, Chiara; Lara, Ana; Stell, Anneliese; Polton, Gerry; Garden, Oliver A

    2014-01-01

    The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3(+) T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.

  7. Engineering CAR-T cells.

    Science.gov (United States)

    Zhang, Cheng; Liu, Jun; Zhong, Jiang F; Zhang, Xi

    2017-01-01

    Chimeric antigen receptor redirected T cells (CAR-T cells) have achieved inspiring outcomes in patients with B cell malignancies, and are now being investigated in other hematologic malignancies and solid tumors. CAR-T cells are generated by the T cells from patients' or donors' blood. After the T cells are expanded and genetically modified, they are reinfused into the patients. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. In this review, we first discuss the structure and evolution of chimeric antigen receptors. We then report on the tools used for production of CAR-T cells. Finally, we address the challenges posed by CAR-T cells.

  8. Aberrant phenotypes in peripheral T cell lymphomas.

    Science.gov (United States)

    Hastrup, N; Ralfkiaer, E; Pallesen, G

    1989-01-01

    Seventy six peripheral T cell lymphomas were examined immunohistologically to test their reactivity with a panel of monoclonal antibodies against 11 T cell associated antigens (CD1-8, CD27, UCHL1, and the T cell antigen receptor). Sixty two (82%) lymphomas showed aberrant phenotypes, and four main categories were distinguished as follows: (i) lack of one or several pan-T cell antigens (49, 64% of the cases); (ii) loss of both the CD4 and CD8 antigens (11, 15% of the cases); (iii) coexpression of the CD4 and CD8 antigens (13, 17% of the cases); and (iv) expression of the CD1 antigen (eight, 11% of the cases). No correlation was seen between the occurrence of aberrant phenotypes and the histological subtype. It is concluded that the demonstration of an aberrant phenotype is a valuable supplement to histological assessment in the diagnosis of peripheral T cell lymphomas. It is recommended that the panel of monoclonal antibodies against T cell differentiation antigens should be fairly large, as apparently any antigen may be lost in the process of malignant transformation. Images Figure PMID:2469701

  9. Dissection of T-cell antigen specificity in human melanoma

    DEFF Research Database (Denmark)

    Andersen, Rikke Sick; Albæk Thrue, Charlotte; Junker, Niels

    2012-01-01

    -associated antigens and applying a novel technology for high-throughput analysis of T-cell responses, we dissected the composition of melanoma-restricted T-cell responses in 63 TIL cultures. T-cell reactivity screens against 175 melanoma-associated epitopes detected 90 responses against 18 different epitopes...... predominantly from differentiation and cancer-testis antigens. Notably, the majority of these responses were of low frequency and tumor-specific T-cell frequencies decreased during rapid expansion. A further notable observation was a large variation in the T-cell specificities detected in cultures established...

  10. Behavior and function of tissue-resident memory T cells.

    Science.gov (United States)

    Ariotti, Silvia; Haanen, John B; Schumacher, Ton N

    2012-01-01

    Our understanding of memory T cell function in mice and men is to date in large part restricted to the behavior of circulating memory T cells. Emerging evidence, however, suggests that in addition to such systemic memory T cell populations, a separate population of locally confined memory T cells is generated at former sites of antigen encounter. Here, we discuss the potential function of these long-term tissue-resident memory T cells (T(TRM)), how such local T cell memory can be maintained for prolonged periods of time, and how the induction of long-term tissue-resident memory T cells may potentially be exploited during vaccination. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. CCL22-specific T Cells

    DEFF Research Database (Denmark)

    Martinenaite, Evelina; Munir Ahmad, Shamaila; Hansen, Morten

    2016-01-01

    Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22-expressing cells by activating specific T cells. We...... analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2- (HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cells in vitro. T cells recognizing an epitope derived from...... the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22-specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using...

  12. TNF activity and T cells.

    Science.gov (United States)

    Mehta, Amit K; Gracias, Donald T; Croft, Michael

    2018-01-01

    TNF (tumor necrosis factor) is both a pro-inflammatory and anti-inflammatory cytokine that is central to the development of autoimmune disease, cancer, and protection against infectious pathogens. As well as a myriad other activities, TNF can be a product of T cells and can act on T cells. Here we review old and new data on the importance of TNF produced by T cells and how TNF signaling via TNFR2 may directly impact alternate aspects of T cell biology. TNF can promote the activation and proliferation of naïve and effector T cells, but also can induce apoptosis of highly activated effector T cells, further determining the size of the pathogenic or protective conventional T cell pool. Moreover, TNF can have divergent effects on regulatory T cells. It can both downregulate their suppressive capacity, but also contribute in other instances to their development or accumulation. Biologics that block TNF or stimulate TNFR2 therefore have the potential to strongly modulate the balance between effector T cells and Treg cells which could impact disease in both positive and negative manners. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. GLYCAN-DIRECTED CAR-T CELLS.

    Science.gov (United States)

    Steentoft, Catharina; Migliorini, Denis; King, Tiffany R; Mandel, Ulla; June, Carl H; Posey, Avery D

    2018-01-23

    Cancer immunotherapy is rapidly advancing in the treatment of a variety of hematopoietic cancers, including pediatric acute lymphoblastic leukemia and diffuse large B cell lymphoma, with chimeric antigen receptor (CAR)-T cells. CARs are genetically encoded artificial T cell receptors that combine the antigen specificity of an antibody with the machinery of T cell activation. However, implementation of CAR technology in the treatment of solid tumors has been progressing much slower. Solid tumors are characterized by a number of challenges that need to be overcome, including cellular heterogeneity, immunosuppressive tumor microenvironment (TME), and, in particular, few known cancer-specific targets. Post-translational modifications that differentially occur in malignant cells generate valid cell surface, cancer-specific targets for CAR-T cells. We previously demonstrated that CAR-T cells targeting an aberrant O-glycosylation of MUC1, a common cancer marker associated with changes in cell adhesion, tumor growth, and poor prognosis, could control malignant growth in mouse models. Here, we discuss the field of glycan-directed CAR-T cells and review the different classes of antibodies specific for glycan-targeting, including the generation of high affinity O-glycopeptide antibodies. Finally, we discuss historic and recently investigated glycan targets for CAR-T cells and provide our perspective on how targeting the tumor glycoproteome and/or glycome will improve CAR-T immunotherapy. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. T-cell responses in malaria

    DEFF Research Database (Denmark)

    Hviid, L; Jakobsen, P H; Abu-Zeid, Y A

    1992-01-01

    vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information......Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria......, and discusses factors affecting the responses of T cells to malaria antigens....

  15. T-cell responses in malaria

    DEFF Research Database (Denmark)

    Hviid, L; Jakobsen, P H; Abu-Zeid, Y A

    1992-01-01

    Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria...... vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information......, and discusses factors affecting the responses of T cells to malaria antigens....

  16. T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness

    NARCIS (Netherlands)

    C.H.J. Lamers (Cor); S. van Steenbergen-Langeveld (Sabine); M. van Brakel (Mandy); C.M. Groot-van Ruijven (Corrien); P.M.M.L. van Elzakker (Pascal); B.A. van Krimpen (Brigitte); S. Sleijfer (Stefan); J.E.M.A. Debets (Reno)

    2014-01-01

    textabstractTherapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T

  17. Isolation of monocytes from leukapheretic products for large-scale GMP-grade generation of cytomegalovirus-specific T-cell lines by means of an automated elutriation device.

    Science.gov (United States)

    Perseghin, Paolo; D'Amico, Giovanna; Dander, Erica; Gaipa, Giuseppe; Dassi, Maria; Biagi, Ettore; Biondi, Andrea

    2008-08-01

    Dendritic cells (DC) act as antigen-presenting cells in immune response-mediated mechanisms against malignant cells and/or viral or fungal pathogens. CD14+ monocytes have been so far isolated by techniques of plastic adherence or by using immunomagnetic methods. Here the effectiveness of a commercially available cell separation system (Elutra, Gambro BCT) in the separation of monocytes and the large-scale production of cytomegalovirus (CMV)-specific T-cell lines were investigated. Six mononuclear cell (MNC) collections were processed with the Elutra system. Monocyte-enriched fraction was differentiated into DCs by addition of granulocyte-macrophage-colony-stimulating factor and interleukin (IL)-4. After 6 days of culture, DCs were matured in the presence of interferon (IFN)-gamma, IFN-alpha, IL-1beta, tumor necrosis factor-alpha, and poly(I:C) and pulsed with a pool of 48 MHC Class I and II-binding CMV peptides. Lymphocytes were then stimulated with mature autologous CMV peptide-pulsed DCs. After elutriation, the mean monocyte yield was 0.89 x 10(9) +/- 0.65 x 10(9), with a 51.0 +/- 31.6 percent recovery and a 51.1 +/- 35.4 percent purity. A significant correlation was observed when basal monocyte content was related to the postelutriation recovery (p < 0.0116). More than 60 percent of plated monocytes were differentiated into DCs, which after pulsing with CMV peptides, were able to stimulate a robust enrichment in CMV antigen-specific T cells in all tested samples (mean percentage of pentamer-positive CD8+ cells, 35% compared to the initial 2%). Our findings might be helpful for an appropriate MNC collection, to maximize the efficiency of the elutriation system and subsequently obtain an optimal monocyte-enriched yield for further DC generation and T-cell stimulation.

  18. Self-reactive T cells

    DEFF Research Database (Denmark)

    Becker, Jürgen C; thor Straten, Per; Andersen, Mads Hald

    2014-01-01

    -proteins expressed in regulatory immune cells have been reported, especially in patients with cancer. The seemingly lack of tolerance toward such proteins is interesting, as it suggests a regulatory function of self-reactive T (srT) cells, which may be important for the fine tuning of the immune system....... In particular, surprising has been the description of cytotoxic srT cells that are able to eliminate normal regulatory immune cells. Such srT cells may be important as effector cells that suppress regulatory suppressor cells. The current knowledge of the nature and function of srT cells is still limited. Still......, the therapeutic targeting of srT cells offers a novel approach to harness immune-regulatory networks in cancer....

  19. Sub-megabase resolution tiling (SMRT array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines

    Directory of Open Access Journals (Sweden)

    Lam Wan L

    2008-01-01

    Full Text Available Abstract Background Hodgkin lymphoma (HL and Anaplastic Large Cell Lymphoma (ALCL, are forms of malignant lymphoma defined by unique morphologic, immunophenotypic, genotypic, and clinical characteristics, but both overexpress CD30. We used sub-megabase resolution tiling (SMRT array-based comparative genomic hybridization to screen HL-derived cell lines (KMH2 and L428 and ALCL cell lines (DEL and SR-786 in order to identify disease-associated gene copy number gains and losses. Results Significant copy number gains and losses were observed on several chromosomes in all four cell lines. Assessment of copy number alterations with 26,819 DNA segments identified an average of 20 genetic alterations. Of the recurrent minimally altered regions identified, 11 (55% were within previously published regions of chromosomal alterations in HL and ALCL cell lines while 9 (45% were novel alterations not previously reported. HL cell lines L428 and KMH2 shared gains in chromosome cytobands 2q23.1-q24.2, 7q32.2-q36.3, 9p21.3-p13.3, 12q13.13-q14.1, and losses in 13q12.13-q12.3, and 18q21.32-q23. ALCL cell lines SR-786 and DEL, showed gains in cytobands 5p15.32-p14.3, 20p12.3-q13.11, and 20q13.2-q13.32. Both pairs of HL and ALCL cell lines showed losses in 18q21.32-18q23. Conclusion This study is considered to be the first one describing HL and ALCL cell line genomes at sub-megabase resolution. This high-resolution analysis allowed us to propose novel candidate target genes that could potentially contribute to the pathogenesis of HL and ALCL. FISH was used to confirm the amplification of all three isoforms of the trypsin gene (PRSS1/PRSS2/PRSS3 in KMH2 and L428 (HL and DEL (ALCL cell lines. These are novel findings that have not been previously reported in the lymphoma literature, and opens up an entirely new area of research that has not been previously associated with lymphoma biology. The findings raise interesting possibilities about the role of signaling

  20. Anaplastic thyroid cancer, tumorigenesis and therapy.

    LENUS (Irish Health Repository)

    O'Neill, J P

    2010-03-01

    Anaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.

  1. Postoperative radiotherapy of supratentorial anaplastic gliomas

    International Nuclear Information System (INIS)

    Wendt, T.G.; Bacherler, B.; Baumer, K.; Rohloff, R.; Willich, N.

    1986-01-01

    Between 1970 and 1983, 149 patients with high grade anaplastic supratentorial gliomas received a postoperative irradiation during primary treatment. 118 out of these patients had an anaplastic astrocytoma, 18 an anaplastic oligodendroglioma, and 13 an anaplastic ependymoma. Most of these patients were treated by irradiation of a great volume with 50 Gy within five weeks, the others by irradiation of the total brain with 50 Gy within five weeks and saturation with 10 Gy within one week. The one-year survival of the total group was 35.5% and the two-year survival 10.6%. Patients at an age of less than 40 years show a significantly longer survival than older patients (one-year survival rates 40% and 30.7%, respectively). Patients suffering from anaplastic tumors with astrocytic and oligodendrocytic differentiation have a comparable prognosis. Patients suffering from anaplastic tumors with ependymal differentiation, however, have prolonged survival times. The therapy results of different treatment methods are discussed using the communications of literature. (orig.) [de

  2. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity.

    Science.gov (United States)

    Heit, Antje; Gebhardt, Friedemann; Lahl, Katharina; Neuenhahn, Michael; Schmitz, Frank; Anderl, Florian; Wagner, Hermann; Sparwasser, Tim; Busch, Dirk H; Kastenmüller, Kathrin

    2008-06-01

    Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.

  3. CD8+ T cells in Leishmania infections: friends or foes?

    Directory of Open Access Journals (Sweden)

    Simona eStager

    2012-01-01

    Full Text Available Host protection against several intracellular pathogens requires the induction of CD8+ T cell responses. CD8+ T cells are potent effector cells that can produce high amounts of pro-inflammatory cytokines and kill infected target cells efficiently. However, a protective role for CD8+ T cells during Leishmania infections is still controversial and largely depends on the infection model. In this review, we discuss the role of CD8+ T cells during various types Leishmania infections, following vaccination, and as potential immunotherapeutic targets.

  4. Pleomorphic xanthoastrocytoma with anaplastic features

    Directory of Open Access Journals (Sweden)

    Cheng ZHI

    2015-08-01

    Full Text Available Objective  To explore the clinical pathological characteristics, immunophenotyping, diagnosis and differential diagnosis and prognosis of pleomorphic xanthoastrocytoma (PXA with anaplastic features.  Methods  HE staining was used for histological observation. The expressions of glial fibrillary acidic protein (GFAP, vimentin (Vim, CD34, epithelial membrane antigen (EMA, progestrone receptor (PR, neurofilment protein (NF, neuronal nuclei (NeuN, synaptophysin (Syn, Nestin (Nes, S-100 protein (S-100, P53 and Ki-67 labeling index were detected by immunohistochemical method. BRAF mutation was detected by polymerase chain reaction (PCR amplification.  Results  A 43-year-old male patient presented with repeatedly paroxysmal tic of limbs and disturbance of consciousness. Cranial MRI revealed multiple abnormal signals in left temporo-occipito-parietal lobe and posterior horn of lateral ventricle, with unclear borderline and cystic degeneration. Surgical removal of the lesion was performed. Histologically, the tumor was biphasic. One part was composed of spindle cells arranged in fascicles or as running water, with weird multinuclear giant cells. Abundant vacuolated lipidized cytoplasm could be seen. Mitosis and "map"-like necrosis were noted. Another part revealed the tumor cells were consistent in size and uniform in distribution, with loose background tissue. Immunohistochemistry showed tumor cells were diffusely positive for GFAP, Vim, S-100, Nes, CD34 and P53, and negative for EMA, Syn, NeuN and NF. Ki-67 labeling index was about 15%. Reticular fiber staining showed abundant reticular fibers in the tumor tissue. BRAF mutation detected by PCR amplification was not found.  Conclusions  Classified as grade Ⅱ in the World Health Organization (WHO classification, the prognosis of PXA is good. A diagnosis of PXA with anaplastic features should be considered when the tumor demonstrates mitotic activity > 5/10 high power field (HPF and/or areas of

  5. Self-presentation of beryllium by BAL CD4+ T cells: T cell-T cell interactions and their potential role in chronic beryllium disease.

    Science.gov (United States)

    Fontenot, Andrew P; Edwards, David M; Chou, Yuan K; Mack, Douglas G; LaTocha, Dorian; Vandenbark, Arthur A; Burrows, Gregory G

    2006-04-01

    Chronic beryllium disease (CBD) is characterized pathologically by granulomatous inflammation in the lung, composed of a large core of epithelioid cells surrounded by a dense shell of CD4+ T cells. Using beryllium-specific CD4+ T cell lines derived from the bronchoalveolar lavage (BAL) fluid of CBD patients, we show that purified CD4+ T cells produced significant amounts of IFN-gamma and TNF-alpha upon exposure to beryllium in the absence of antigen-presenting cells (APC). However, unlike BAL T cells stimulated by beryllium in the presence of APC, self-presentation by BAL T cells did not induce detectable IL-2 production, and in its absence these activated T cells die from programmed cell death. Resting BAL CD4+ T cells constitutively express high levels of HLA-DP, lymphocyte function-associated antigen 1 (LFA-1) and ICAM-3. When stimulated with beryllium/APC, the adhesion molecule ICAM-1 was up-regulated, as well as several costimulation molecules including CD28, OX-40 (CD134), 4-1-BB (CD137) and B7-1 (CD80). Notably, CD28 was not up-regulated during self-presentation by BAL T cells, and these cells do not express OX-40L, suggesting that lack of appropriate costimulation was responsible for programmed cell death observed upon beryllium self-presentation. Restricting anti-MHC class II mAb completely eliminated beryllium-induced T cell proliferation during self-presentation and significantly reduced IFN-gamma and TNF-alpha production. Our data demonstrate for the first time that self-presentation by BAL T cells in response to beryllium can occur ex vivo, in the absence of professional APC, with a specific dependence on T cell-expressed MHC class II molecules and exogenous IL-2 for survival.

  6. Genetic engineering with T cell receptors.

    Science.gov (United States)

    Zhang, Ling; Morgan, Richard A

    2012-06-01

    In the past two decades, human gene transfer research has been translated from a laboratory technology to clinical evaluation. The success of adoptive transfer of tumor-reactive lymphocytes to treat the patients with metastatic melanoma has led to new strategies to redirect normal T cells to recognize tumor antigens by genetic engineering with tumor antigen-specific T cell receptor (TCR) genes. This new strategy can generate large numbers of defined antigen-specific cells for therapeutic application. Much progress has been made to TCR gene transfer systems by optimizing gene expression and gene transfer protocols. Vector and protein modifications have enabled excellent expression of introduced TCR chains in human lymphocytes with reduced mis-pairing between the introduced and endogenous TCR chains. Initial clinical studies have demonstrated that TCR gene-engineered T cells could mediate tumor regression in vivo. In this review, we discuss the progress and prospects of TCR gene-engineered T cells as a therapeutic strategy for treating patients with melanoma and other cancers. Published by Elsevier B.V.

  7. Viral inoculum dose impacts memory T-cell inflation.

    Science.gov (United States)

    Redeker, Anke; Welten, Suzanne P M; Arens, Ramon

    2014-04-01

    Memory T-cell inflation develops during certain persistent viral infections and is characterized by the accumulation and maintenance of large numbers of effector-memory T cells, albeit with varying degrees in size and phenotype among infected hosts. The underlying mechanisms that control memory T-cell inflation are not yet fully understood. Here, we dissected CMV-specific memory T-cell formation and its connection to the initial infectious dose by varying the inoculum size. After low dose inoculum with mouse CMV, the accumulation of inflationary memory T cells was severely hampered and correlated with reduced reservoirs of latent virus in nonhematopoietic cells and diminished antigen-driven T-cell proliferation. Moreover, lowering of the initial viral dose turned the characteristic effector memory-like inflationary T cells into more central memory-like cells as evidenced by the cell-surface phenotype of CD27(high) , CD62L(+) , CD127(+) , and KLRG1(-) , and by improved secondary expansion potential. These data show the impact of the viral inoculum on the degree of memory T-cell inflation and provide a rationale for the observed variation of human CMV-specific T-cell responses in terms of magnitude and phenotype. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. γδ T Cell Immunotherapy—A Review

    Directory of Open Access Journals (Sweden)

    Hirohito Kobayashi

    2015-02-01

    Full Text Available Cancer immunotherapy utilizing Vγ9Vδ2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. Vγ9Vδ2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of Vγ9Vδ2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation-induced Vγ9Vδ2 T cell anergy and a decrease in the number of peripheral blood Vγ9Vδ2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand Vγ9Vδ2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood Vγ9Vδ2 T cells. In this article, we review the clinical studies and reports targeting Vγ9Vδ2 T cells and discuss the development and improvement of Vγ9Vδ2 T cell-based cancer immunotherapy.

  9. Cerebral oligodendroglioma: MR features indicating anaplastic changes

    International Nuclear Information System (INIS)

    Choi, Choong Gon; Chang, Kee Hyun; Han, Moon Hee; Chi, Je Geun; Yoon, Hyun Ki

    1995-01-01

    The purpose of this study is to find helpful MR findings for predicting anaplastic oligodendrogliomas. Retrospective analysis of 46 MR images and 37 CT scans was performed for 46 patients with pathologically-proven cerebral oligodendrogliomas. A neuropathologist graded the tumors as one of low-grade (n = 16), intermediate-grade (n = 12), or anaplastic oligodendroglioma (n 18). MR imaging features were retrospectively analysed with respect to histologic grading of the tumors. Contrast enhancement was observed always in anaplastic group (17/17), in a portion of intermediate-grade group (4/10) but not in low-grade group (0/4). Peritumoral edema was observed infrequently in anaplastic group (4/18) or intermediate-grade group (1/12). Cystic changes (25/46) or calcifications on CT Scans (14/37) were not related with histologic grading. Grossly identifiable hemorrhage was rare in this series (2/46). Among the various imaging features, only tumor enhancement and peritumoral edema were statistically significant for trend test (ρ < 0.05). When considering the diagnosis of oligodendrogliomas, the presence of contrast enhancement or peritumoral edema is a helpful features suggesting anaplastic oligodendrogliomas

  10. Theoretical models for T-cell vaccination

    NARCIS (Netherlands)

    Boer, R.J. de; Borghans, J.A.M.

    1995-01-01

    T cell vaccination (TCV) is a term for a whole collection of phenomena in which the injection of T cells provides protection against autoimmunity. Vaccination with T cells has been investigated for several autoimmune diseases, including experimental autoimmune encephalomyelitis, adjuvant

  11. Elementary Steps in T Cell Receptor Triggering

    OpenAIRE

    Dushek, Omer

    2012-01-01

    The mechanism by which antigen binding to the T cell antigen receptor (TCR) generates intracellular signaling, a process termed TCR triggering, is incompletely understood. A large body of experimental evidence has implicated multiple biophysical/biochemical effects and multiple molecules in the process of TCR triggering, which likely reflect the uniquely demanding role of the TCR in recognizing diverse antigenic ligands. In this perspective, I propose that breaking down the process of TCR tri...

  12. CD8+ T cells in cutaneous T-cell lymphoma: expression of cytotoxic proteins, Fas Ligand, and killing inhibitory receptors and their relationship with clinical behavior

    NARCIS (Netherlands)

    Vermeer, M. H.; van Doorn, R.; Dukers, D.; Bekkenk, M. W.; Meijer, C. J.; Willemze, R.

    2001-01-01

    We investigated the number, phenotype, and prognostic significance of CD8+ T cells in patients with mycosis fungoides (MF) and CD30- primary cutaneous large T-cell lymphoma (PCLTCL). Immunohistochemical stainings for CD8, granzyme B (GrB), T cell-restricted intracellular antigen (TIA-1), Fas ligand

  13. Anaplastic meningioma: The dark side of meningiomas

    Directory of Open Access Journals (Sweden)

    Andreea Cioca

    2017-06-01

    Full Text Available Anaplastic meningioma is a rare malignant tumor of the meninges, with a very aggressive behavior and a grim prognosis. Here we report a case of a 64-year old man which presented to the neurosurgery department with motor deficit in the right hemi–body, loss of speech and disorientation. Magnetic resonance imaging detected a mass located in the left frontal lobe that measured 7/8/7 cm, leading to the conclusion that surgery is necessary. Microscopic examination of the tumor showed great number of hypercellular areas with a high mitotic index, and focal necrosis with psammoma bodies. Using a panel of antibodies such as EMA, vimentin, CD34 GFAP, pancytokeratin and Ki67, we concluded that he final diagnosis was anaplastic meningioma, WHO grade III. Due to its morphological similarity with other tumors, the diagnosis of anaplastic meningioma may be challenging.

  14. Anaplastic hemangiopericytoma of eyelid: An unusual location

    Directory of Open Access Journals (Sweden)

    Pradeep Ventrapati

    2017-01-01

    Full Text Available Hemangiopericytomas (HPCs are rare soft tissue tumors. The eyelid is a very uncommon site for these tumors, and an anaplastic variant of HPC in the eyelid has not been reported before. A 44-year-old male presented with complaints of slowly progressive, painless swelling on the inner aspect of the left upper eyelid for 9 months. He underwent local excision of the swelling and histopathology revealed a WHO Grade III anaplastic HPC. Whole body 18 F-fluorodeoxyglucose positron emission tomography-computed tomography done postoperatively did not show any evidence of local or distant disease. The patient was planned for adjuvant radiotherapy of 60 Gy in 30 fractions over 6 weeks in view of high grade of histopathology and doubtful margins. He is disease free at the time of the last follow-up. To the best of our knowledge, this is the first case of anaplastic HPC of eyelid being reported in English literature.

  15. Anti-regulatory T cells

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2017-01-01

    Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...... responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells...

  16. Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

    Science.gov (United States)

    2014-11-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

  17. Round cell anaplastic carcinoma of the pancreas

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jae Hoon; Lee, Dong Ho; Ko, Young Tae; Yang, Moon Ho [Kyung Hee University Hospital, Seoul (Korea, Republic of)

    1989-02-15

    Ultrasonography of the upper abdomen disclosed an oval well defined mass in the pancreas. Round cell anaplastic carcinoma is one of sarcomatoid pancreatic carcinoma, microscopically characterized by monotonous sheaths of small round plump cells with rare giant cells and thus more or less reminiscent of malignant lymphoma. Whether this tumor is of ductal or acinar cell origin remains to be determined. Clinically, this tumor does not differ significantly from ordinary adenocarcinoma of the pancreas. We report a cases of round cell anaplastic carcinoma and describe the CT and sonographic findings, and discuss the differential points from other solid pancreatic tumors.

  18. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer.

    Directory of Open Access Journals (Sweden)

    Todd M Brusko

    2010-07-01

    Full Text Available Therapies directed at augmenting regulatory T cell (Treg activities in vivo as a systemic treatment for autoimmune disorders and transplantation may be associated with significant off-target effects, including a generalized immunosuppression that may compromise beneficial immune responses to infections and cancer cells. Adoptive cellular therapies using purified expanded Tregs represents an attractive alternative to systemic treatments, with results from animal studies noting increased therapeutic potency of antigen-specific Tregs over polyclonal populations. However, current methodologies are limited in terms of the capacity to isolate and expand a sufficient quantity of endogenous antigen-specific Tregs for therapeutic intervention. Moreover, FOXP3+ Tregs fall largely within the CD4+ T cell subset and are thus routinely MHC class II-specific, whereas class I-specific Tregs may function optimally in vivo by facilitating direct tissue recognition.To overcome these limitations, we have developed a novel means for generating large numbers of antigen-specific Tregs involving lentiviral T cell receptor (TCR gene transfer into in vitro expanded polyclonal natural Treg populations. Tregs redirected with a high-avidity class I-specific TCR were capable of recognizing the melanoma antigen tyrosinase in the context of HLA-A*0201 and could be further enriched during the expansion process by antigen-specific reactivation with peptide loaded artificial antigen presenting cells. These in vitro expanded Tregs continued to express FOXP3 and functional TCRs, and maintained the capacity to suppress conventional T cell responses directed against tyrosinase, as well as bystander T cell responses. Using this methodology in a model tumor system, murine Tregs designed to express the tyrosinase TCR effectively blocked antigen-specific effector T cell (Teff activity as determined by tumor cell growth and luciferase reporter-based imaging.These results support the

  19. T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells.

    Directory of Open Access Journals (Sweden)

    Gang Li

    Full Text Available Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62L(highCD44(low Sca-1(+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells.

  20. Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

    Directory of Open Access Journals (Sweden)

    Tomohiro Tanaka

    Full Text Available The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.

  1. Comorbidity as an independent prognostic factor in elderly patients with peripheral T-cell lymphoma

    Directory of Open Access Journals (Sweden)

    Zhao H

    2016-03-01

    Full Text Available Haifeng Zhao,1,* Tengteng Wang,1,* Yafei Wang,1 Yong Yu,1 Xiaofan Wang,1 Zhigang Zhao,1 Hongliang Yang,1 Bei Yan,2 Xiaoxiong Wu,2 Wanming Da,3 Yizhuo Zhang1,* 1Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 2Department of Hematology, First Affiliated Hospital of Chinese People’s Liberation Army General Hospital, 3Department of Hematology, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: The aim of the present study was to investigate the role of comorbidities in the outcomes of patients with peripheral T-cell lymphoma (PTCL in a Chinese population. Fifty-six newly diagnosed PTCL patients aged >60 years were enrolled in our institution between April 2008 and August 2014. Medical record details including clinical parameters, pathological status, and treatment were reviewed. Prognostic factors were assessed using univariate and multivariate analyses. Forty-one (73.2% patients with PTCL, not otherwise specified (PTCL-NOS, nine (16.1% with angioimmunoblastic T-cell lymphoma, and six (10.7% with anaplastic large cell lymphoma were recruited in this study. Twenty-eight (50% had at least one comorbidity. Univariate analysis showed that an Eastern Cooperative Oncology Group score of 2–4, the presence of B symptoms, an International Prognostic Index (IPI score of 3–5, and a Charlson Comorbidity Index (CCI score ≥2 were significantly associated with shortened overall survival (OS, whereas the presence of B symptoms, an IPI of 3–5, and a CCI ≥2 were associated with worsened progression-free survival (PFS. Multivariate analysis indicated that a high CCI (≥2 and a high IPI (3–5 were poor independent prognostic factors for OS and PFS in the elderly patients with PTCL. Comorbidity was identified as a new

  2. Fish T cells: recent advances through genomics

    Science.gov (United States)

    Laing, Kerry J.; Hansen, John D.

    2011-01-01

    This brief review is intended to provide a concise overview of the current literature concerning T cells, advances in identifying distinct T cell functional subsets, and in distinguishing effector cells from memory cells. We compare and contrast a wealth of recent progress made in T cell immunology of teleost, elasmobranch, and agnathan fish, to knowledge derived from mammalian T cell studies. From genome studies, fish clearly have most components associated with T cell function and we can speculate on the presence of putative T cell subsets, and the ability to detect their differentiation to form memory cells. Some recombinant proteins for T cell associated cytokines and antibodies for T cell surface receptors have been generated that will facilitate studying the functional roles of teleost T cells during immune responses. Although there is still a long way to go, major advances have occurred in recent years for investigating T cell responses, thus phenotypic and functional characterization is on the near horizon.

  3. Human T Cell Memory: A Dynamic View

    Directory of Open Access Journals (Sweden)

    Derek C. Macallan

    2017-02-01

    Full Text Available Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells. Clonal survival is achieved by balancing proliferation, death and differentiation rates within and between identifiable phenotypic pools; such pools correspond broadly to sequential stages in the linear differentiation pathway. Each pool has its own characteristic kinetics, but only when considered as a population; single cells exhibit considerable heterogeneity. In humans, we tend to concentrate on circulating cells, but memory T cells in non-lymphoid tissues and bone marrow are increasingly recognised as critical for immune defence; their kinetics, however, remain largely unexplored. Considering vaccination from this viewpoint shifts the focus from the size of the primary response to the survival of the clone and enables identification of critical system pinch-points and opportunities to improve vaccine efficacy.

  4. Human T Cell Memory: A Dynamic View

    Science.gov (United States)

    Macallan, Derek C.; Borghans, José A. M.; Asquith, Becca

    2017-01-01

    Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells. Clonal survival is achieved by balancing proliferation, death and differentiation rates within and between identifiable phenotypic pools; such pools correspond broadly to sequential stages in the linear differentiation pathway. Each pool has its own characteristic kinetics, but only when considered as a population; single cells exhibit considerable heterogeneity. In humans, we tend to concentrate on circulating cells, but memory T cells in non-lymphoid tissues and bone marrow are increasingly recognised as critical for immune defence; their kinetics, however, remain largely unexplored. Considering vaccination from this viewpoint shifts the focus from the size of the primary response to the survival of the clone and enables identification of critical system pinch-points and opportunities to improve vaccine efficacy. PMID:28165397

  5. Aire and T cell development.

    Science.gov (United States)

    Anderson, Mark S; Su, Maureen A

    2011-04-01

    In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Signal transduction by HLA class II antigens expressed on activated T cells

    DEFF Research Database (Denmark)

    Ødum, Niels; Martin, P J; Schieven, G L

    1991-01-01

    Human T cells express HLA class II antigens upon activation. Although activated, class II+ T cells can present alloantigens under certain circumstances, the functional role of class II antigens on activated T cells remains largely unknown. Here, we report that cross-linking of HLA-DR molecules...

  7. Secondary cutaneous Epstein-Barr virus-associated diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma: a case report and review of literature

    Directory of Open Access Journals (Sweden)

    Yang Qing-Xu

    2012-01-01

    Full Text Available Abstract Only a few cases of extranodal Epstein-Barr virus (EBV-associated B-cell lymphomas arising from patients with angioimmunoblastic T-cell lymphoma (AITL have been described. We report a case of AITL of which secondary cutaneous EBV-associated diffuse large B-cell lymphoma (DLBCL developed after the initial diagnosis of AITL. A 65-year-old Chinese male patient was diagnosed as AITL based on typical histological and immunohistochemical characteristics in biopsy of the enlarged right inguinal lymph nodes. The patient initially received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, prednisone, but his symptoms did not disappear. Nineteen months after initial diagnosis of AITL, the patient was hospitalized again because of multiple plaques and nodules on the skin. The skin biopsy was performed, but this time the tumor was composed of large, polymorphous population of lymphocytes with CD20 and CD79a positive on immunohistochemical staining. The tumor cells were strong positive for EBER by in situ hybridization. The findings of skin biopsy were compatible with EBV-associated DLBCL. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab was then administered, resulting in partial response of the disease with pancytopenia and suppression of cellular immunity. To our knowledge, this is the first case of cutaneous EBV-associated DLBCL originated from AITL in Chinese pepole. We suggest the patients with AITL should perform lymph node and skin biopsies regularly in the course of the disease to detect the progression of secondary lymphomas. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1197421158639299

  8. Selective expansion of human gamma delta T cells by monocytes infected with live Mycobacterium tuberculosis.

    OpenAIRE

    Havlir, D V; Ellner, J J; Chervenak, K A; Boom, W H

    1991-01-01

    Gamma delta (gamma delta) T cell receptor (TCR) expressing T cells comprise 3% of human peripheral blood lymphocytes, yet their role in the immune response remains largely unknown. There is evidence both in humans and in animal models that these cells participate in the immune response to mycobacterial antigens. In mice, exposure to mycobacterial antigens leads to the expansion of gamma delta T cells in draining lymph nodes and lungs. In humans, gamma delta T cell lines with reactivity to myc...

  9. A Systematic Review and Meta-Analysis of Front-line Anthracycline-Based Chemotherapy Regimens for Peripheral T-Cell Lymphoma

    Science.gov (United States)

    AbouYabis, Abeer N.; Shenoy, Pareen J.; Sinha, Rajni; Flowers, Christopher R.; Lechowicz, Mary Jo

    2011-01-01

    Anthracycline-based chemotherapy remains standard treatment for peripheral T-cell lymphoma (PTCL) although its benefits have been questioned. We performed systematic literature review and meta-analyses examining the complete response (CR) and overall survival (OS) rates for patients with PTCL. The CR rate for PTCL patients ranged from 35.9% (95% CI 23.4–50.7%) for enteropathy-type T-cell lymphoma (ETTL) to 65.8% (95% CI 54.0–75.9%) for anaplastic large cell lymphoma (ALCL). The 5-year OS was 38.5% (95% CI 35.5–41.6%) for all PTCL patients and ranged from 20.3% (95% CI 12.5–31.2%) for ETTL to 56.5% (95% CI 42.8–69.2%) for ALCL. These data suggest that there is marked heterogeneity across PTCL subtypes in the benefits of anthracycline-based chemotherapy. While anthracyclines produce CR in half of PTCL patients, this yields reasonable 5-year OS for patients with ALCL but not for those with PTCL-NOS or ETTL. Novel agents and regimens are needed to improve outcomes for these patients. PMID:22084700

  10. Ex vivo immunosuppressive effects of mesenchymal stem cells on Crohn's disease mucosal T cells are largely dependent on indoleamine 2,3-dioxygenase activity and cell-cell contact.

    Science.gov (United States)

    Ciccocioppo, Rachele; Cangemi, Giuseppina C; Kruzliak, Peter; Gallia, Alessandra; Betti, Elena; Badulli, Carla; Martinetti, Miryam; Cervio, Marila; Pecci, Alessandro; Bozzi, Valeria; Dionigi, Paolo; Visai, Livia; Gurrado, Antonella; Alvisi, Costanza; Picone, Cristina; Monti, Manuela; Bernardo, Maria E; Gobbi, Paolo; Corazza, Gino R

    2015-07-24

    Crohn's disease (CD) is a disabling chronic enteropathy sustained by a harmful T-cell response toward antigens of the gut microbiota in genetically susceptible subjects. Growing evidence highlights the safety and possible efficacy of mesenchymal stem cells (MSCs) as a new therapeutic tool for this condition. Therefore, we aimed to investigate the effects of bone marrow-derived MSCs on pathogenic T cells with a view to clinical application. T-cell lines from both inflamed and non-inflamed colonic mucosal specimens of CD patients and from healthy mucosa of control subjects were grown with the antigen muramyl-dipeptide in the absence or presence of donors' MSCs. The MSC effects were evaluated in terms of T-cell viability, apoptotic rate, proliferative response, immunophenotype, and cytokine profile. The role of the indoleamine 2,3-dioxygenase (IDO) was established by adding a specific inhibitor, the 1-methyl-DL-tryptophan, and by using MSCs transfected with the small interfering RNA (siRNA) targeting IDO. The relevance of cell-cell contact was evaluated by applying transwell membranes. A significant reduction in both cell viability and proliferative response to muramyl-dipeptide, with simultaneous increase in the apoptotic rate, was found in T cells from both inflamed and non-inflamed CD mucosa when co-cultured with MSCs and was reverted by inhibiting IDO activity and expression. A reduction of the activated CD4(+)CD25(+) subset and increase of the CD3(+)CD69(+) population were also observed when T-cell lines from CD mucosa were co-cultured with MSCs. In parallel, an inhibitory effect was evident on the expression of the pro-inflammatory cytokines tumor necrosis factor-α, interferon-γ, interleukin-17A and -21, whereas that of the transforming growth factor-β and interleukin-6 were increased, and production of the tolerogenic molecule soluble HLA-G was high. These latter effects were almost completely eliminated by blocking the IDO, whose activity was upregulated in

  11. T Cell Aging: A Review of the Transcriptional Changes Determined from Genome-Wide Analysis

    Science.gov (United States)

    Chen, Guobing; Lustig, Ana; Weng, Nan-ping

    2013-01-01

    Age carries a detrimental impact on T cell function. In the past decade, analyses of the genome-scale transcriptional changes of T cells during aging have yielded a large amount of data and provided a global view of gene expression changes in T cells from aged hosts as well as subsets of T cells accumulated with age. Here, we aim to review the changes of gene expression in thymocytes and peripheral mature T cells, as well as the subsets of T cells accumulated with age, and discuss the gene networks and signaling pathways that are altered with aging in T cells. We also discuss future direction for furthering the understanding of the molecular basis of gene expression alterations in aged T cells, which could potentially provide opportunities for gene-based clinical interventions. PMID:23730304

  12. Tracing T cell differentiation by genetic barcoding

    NARCIS (Netherlands)

    Heijst, Jeroen Waltherus Johannes van

    2010-01-01

    Following antigen encounter, activated T cells can give rise to functionally distinct T cell subsets. Understanding how different T cell subsets arise requires technologies that can monitor the developmental potential of single precursor cells (chapter 2). This thesis describes the development and

  13. PD-L1-specific T cells

    DEFF Research Database (Denmark)

    Ahmad, Shamaila Munir; Borch, Troels Holz; Hansen, Morten

    2016-01-01

    -specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy...... for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses...

  14. T cell exhaustion and Interleukin 2 downregulation.

    Science.gov (United States)

    Balkhi, Mumtaz Y; Ma, Qiangzhong; Ahmad, Shazia; Junghans, Richard P

    2015-02-01

    T cells reactive to tumor antigens and viral antigens lose their reactivity when exposed to the antigen-rich environment of a larger tumor bed or viral load. Such non-responsive T cells are termed exhausted. T cell exhaustion affects both CD8+ and CD4+ T cells. T cell exhaustion is attributed to the functional impairment of T cells to produce cytokines, of which the most important may be Interleukin 2 (IL2). IL2 performs functions critical for the elimination of cancer cells and virus infected cells. In one such function, IL2 promotes CD8+ T cell and natural killer (NK) cell cytolytic activities. Other functions include regulating naïve T cell differentiation into Th1 and Th2 subsets upon exposure to antigens. Thus, the signaling pathways contributing to T cell exhaustion could be linked to the signaling pathways contributing to IL2 loss. This review will discuss the process of T cell exhaustion and the signaling pathways that could be contributing to T cell exhaustion. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Regulation of T cell priming by lymphoid stroma.

    Directory of Open Access Journals (Sweden)

    Omar Khan

    Full Text Available The priming of immune T cells by their interaction with dendritic cells (DCs in lymph nodes (LN, one of the early events in productive adaptive immune responses, occurs on a scaffold of lymphoid stromal cells, which have largely been seen as support cells or sources of chemokines and homeostatic growth factors. Here we show that murine fibroblastic reticular cells (FRCs, isolated from LN of B6 mice, play a more direct role in the immune response by sensing and modulating T cell activation through their upregulation of inducible nitric oxide synthase (iNOS in response to early T cell IFNγ production. Stromal iNOS, which only functions in very close proximity, attenuates responses to inflammatory DC immunization but not to other priming regimens and preferentially affects Th1 cells rather than Th2. The resultant nitric oxide production does not affect T cell-DC coupling or initial calcium signaling, but restricts homotypic T cell clustering, cell cycle progression, and proliferation. Stromal feedback inhibition thus provides basal attenuation of T cell responses, particularly those characterized by strong local inflammatory cues.

  16. Human immunodeficiencies related to APC/T cell interaction

    Directory of Open Access Journals (Sweden)

    Marinos eKallikourdis

    2015-08-01

    Full Text Available The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APC in the T cell area of secondary lymphoid organs and the formation of highly organized inter-cellular junctions referred to as the immune synapses. In vivo live-cell imaging of APC-T cell interactions combined to functional studies unveiled that T cell fate is dictated, in large part, by the stability of the initial contact. Immune cell interaction is equally important during delivery of T cell help to B cells and for the killing of target cells by cytotoxic T cells and NK cells. The critical role of contact dynamics and synapse stability on the immune response is well illustrated by human immune deficiencies in which disease pathogenesis is linked to altered adhesion or defective cross-talk between the synaptic partners. Here we will discuss in details the mechanisms of defective APC-T cell communications in Wiskott-Aldrich syndrome (WAS and in warts, hypogammaglobulinemia, infections, myelokathexis syndrome (WHIM. In addition, we will summarize the evidences pointing to a compromised conjugate formation in WIP deficiency, DOCK8 deficiency and X-linked lymphoproliferative syndrome.

  17. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

    DEFF Research Database (Denmark)

    Strønen, Erlend; Toebes, Mireille; Kelderman, Sander

    2016-01-01

    Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies...... to broaden neoantigen-specific T cell responses are therefore attractive. We found that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11 of 57 predicted human leukocyte antigen (HLA)-A*02:01-binding epitopes from three patients. Many of the T...... a rationale for the use of such "outsourced" immune responses in cancer immunotherapy....

  18. Memory B and T cells.

    Science.gov (United States)

    Vitetta, E S; Berton, M T; Burger, C; Kepron, M; Lee, W T; Yin, X M

    1991-01-01

    Three remarkable and unique features of the immune system are specificity, diversity, and memory. Immunological memory involves both T and B cells and results in a secondary antibody response that is faster, of higher affinity, and results in the secretion of non-IgM isotypes of Ig. In this review we discuss the properties of memory T and B cells, their specific receptors, and the events which occur both in the nucleus and on the cell surface during generation and activation of these cells. Although memory T and B cells use different mechanisms to elaborate memory, there are a number of interesting analogies: lymphokines vs antibodies and affinity maturation of B cell antigen receptors vs upregulation of adhesion molecules on T cells. Finally, we discuss the importance of these cells in health and disease and suggest what impact additional information about these cells might have on the manipulation of the immune response.

  19. T cell resistance to activation by dendritic cells requires long-term culture in simulated microgravity

    Science.gov (United States)

    Bradley, Jillian H.; Stein, Rachel; Randolph, Brad; Molina, Emily; Arnold, Jennifer P.; Gregg, Randal K.

    2017-11-01

    Immune impairment mediated by microgravity threatens the success of space exploration requiring long-duration spaceflight. The cells of most concern, T lymphocytes, coordinate the host response against microbial and cancerous challenges leading to elimination and long-term protection. T cells are activated upon recognition of specific microbial peptides bound on the surface of antigen presenting cells, such as dendritic cells (DC). Subsequently, this engagement results in T cell proliferation and differentiation into effector T cells driven by autocrine interleukin-2 (IL-2) and other cytokines. Finally, the effector T cells acquire the weaponry needed to destroy microbial invaders and tumors. Studies conducted on T cells during spaceflight, or using Earth-based culture systems, have shown reduced production of cytokines, proliferation and effector functions as compared to controls. This may account for the cases of viral reactivation events and opportunistic infections associated with astronauts of numerous missions. This work has largely been based upon the outcome of T cell activation by stimulatory factors that target select T cell signaling pathways rather than the complex, signaling events related to the natural process of antigen presentation by DC. This study tested the response of an ovalbumin peptide-specific T cell line, OT-II TCH, to activation by DC when the T cells were cultured 24-120 h in a simulated microgravity (SMG) environment generated by a rotary cell culture system. Following 72 h culture of T cells in SMG (SMG-T) or control static (Static-T) conditions, IL-2 production by the T cells was reduced in SMG-T cells compared to Static-T cells upon stimulation by phorbol 12-myristate 13-acetate (PMA) and ionomycin. However, when the SMG-T cells were stimulated with DC and peptide, IL-2 was significantly increased compared to Static-T cells. Such enhanced IL-2 production by SMG-T cells peaked at 72 h SMG culture time and decreased thereafter. When

  20. T cell resistance to activation by dendritic cells requires long-term culture in simulated microgravity.

    Science.gov (United States)

    Bradley, Jillian H; Stein, Rachel; Randolph, Brad; Molina, Emily; Arnold, Jennifer P; Gregg, Randal K

    2017-11-01

    Immune impairment mediated by microgravity threatens the success of space exploration requiring long-duration spaceflight. The cells of most concern, T lymphocytes, coordinate the host response against microbial and cancerous challenges leading to elimination and long-term protection. T cells are activated upon recognition of specific microbial peptides bound on the surface of antigen presenting cells, such as dendritic cells (DC). Subsequently, this engagement results in T cell proliferation and differentiation into effector T cells driven by autocrine interleukin-2 (IL-2) and other cytokines. Finally, the effector T cells acquire the weaponry needed to destroy microbial invaders and tumors. Studies conducted on T cells during spaceflight, or using Earth-based culture systems, have shown reduced production of cytokines, proliferation and effector functions as compared to controls. This may account for the cases of viral reactivation events and opportunistic infections associated with astronauts of numerous missions. This work has largely been based upon the outcome of T cell activation by stimulatory factors that target select T cell signaling pathways rather than the complex, signaling events related to the natural process of antigen presentation by DC. This study tested the response of an ovalbumin peptide-specific T cell line, OT-II TCH, to activation by DC when the T cells were cultured 24-120 h in a simulated microgravity (SMG) environment generated by a rotary cell culture system. Following 72 h culture of T cells in SMG (SMG-T) or control static (Static-T) conditions, IL-2 production by the T cells was reduced in SMG-T cells compared to Static-T cells upon stimulation by phorbol 12-myristate 13-acetate (PMA) and ionomycin. However, when the SMG-T cells were stimulated with DC and peptide, IL-2 was significantly increased compared to Static-T cells. Such enhanced IL-2 production by SMG-T cells peaked at 72 h SMG culture time and decreased thereafter

  1. A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells.

    Science.gov (United States)

    Ersching, Jonatan; Basso, Alexandre Salgado; Kalich, Vera Lucia Garcia; Bortoluci, Karina Ramalho; Rodrigues, Maurício M

    2016-06-01

    Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections.

  2. A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells

    Science.gov (United States)

    Ersching, Jonatan; Basso, Alexandre Salgado; Kalich, Vera Lucia Garcia; Bortoluci, Karina Ramalho

    2016-01-01

    Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections. PMID:27332899

  3. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses.

    Science.gov (United States)

    Kursar, Mischo; Bonhagen, Kerstin; Fensterle, Joachim; Köhler, Anne; Hurwitz, Robert; Kamradt, Thomas; Kaufmann, Stefan H E; Mittrücker, Hans-Willi

    2002-12-16

    CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

  4. γδ T cells as a potential tool in colon cancer immunotherapy.

    Science.gov (United States)

    Ramutton, Thiranut; Buccheri, Simona; Dieli, Francesco; Todaro, Matilde; Stassi, Giorgio; Meraviglia, Serena

    2014-01-01

    γδ T cells are capable of recognizing tumor cells and exert potent cellular cytotoxicity against a large range of tumors, including colon cancer. However, tumors utilize numerous strategies to escape recognition or killing by patrolling γδ T cells, such a downregulation of NKG2D ligands, MICA/B and ULBPs. Therefore, the combined upregulation of T-cell receptorand NKG2D ligands on tumor cells and induction of NKG2D expression on γδ T cells may greatly enhance tumor killing and unlock the functions of γδ T cells. Here, we briefly review current data on the mechanisms of γδ T-cell recognition and killing of colon cancer cells and propose that γδ T cells may represent a promising target for the design of novel and highly innovative immunotherapy in patients with colon cancer.

  5. Driving CAR T-cells forward

    Science.gov (United States)

    Jackson, Hollie J.; Rafiq, Sarwish; Brentjens, Renier J.

    2017-01-01

    The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting. PMID:27000958

  6. T Cell Exhaustion During Persistent Viral Infections

    Science.gov (United States)

    Kahan, Shannon M.; Wherry, E. John; Zajac, Allan J.

    2015-01-01

    Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control. PMID:25620767

  7. Asymptomatic memory CD8+ T cells

    Science.gov (United States)

    Khan, Arif Azam; Srivastava, Ruchi; Lopes, Patricia Prado; Wang, Christine; Pham, Thanh T; Cochrane, Justin; Thai, Nhi Thi Uyen; Gutierrez, Lucas; BenMohamed, Lbachir

    2014-01-01

    Generation and maintenance of high quantity and quality memory CD8+ T cells determine the level of protection from viral, bacterial, and parasitic re-infections, and hence constitutes a primary goal for T cell epitope-based human vaccines and immunotherapeutics. Phenotypically and functionally characterizing memory CD8+ T cells that provide protection against herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections, which cause blinding ocular herpes, genital herpes, and oro-facial herpes, is critical for better vaccine design. We have recently categorized 2 new major sub-populations of memory symptomatic and asymptomatic CD8+ T cells based on their phenotype, protective vs. pathogenic function, and anatomical locations. In this report we are discussing a new direction in developing T cell-based human herpes vaccines and immunotherapeutics based on the emerging new concept of “symptomatic and asymptomatic memory CD8+ T cells.” PMID:24499824

  8. Human Naive and Memory T Cells Display Opposite Migratory Responses to Sphingosine-1 Phosphate.

    Science.gov (United States)

    Drouillard, Annabelle; Neyra, Antoinette; Mathieu, Anne-Laure; Marçais, Antoine; Wencker, Mélanie; Marvel, Jacqueline; Belot, Alexandre; Walzer, Thierry

    2018-01-15

    The role of sphingosine-1 phosphate (S1P) in leukocyte trafficking has been well deciphered in mice but remains largely unaddressed in humans. In this study, we assessed the ex vivo response to S1P of primary human T cell subsets. We found that tonsil but not blood leukocytes were responsive to S1P gradients, suggesting that T cell responsiveness is regulated during their recirculation in vivo. Tonsil naive T cells were readily chemoattracted by S1P in an FTY720-sensitive, S1PR1-dependent manner. Surprisingly, S1P had the opposite effect on effector memory T cells, resident memory T cells, and recently activated T cells, inhibiting their spontaneous or chemokine-induced migration. This inhibition was also more pronounced for CD4 T cells than for CD8 T cell subsets, and was dependent on S1PR2, as shown using the S1PR2 antagonist JTE-013. S1PR1 was progressively downregulated during T cell differentiation whereas S1PR2 expression remained stable. Our results suggest that the ratio between S1PR1 and S1PR2 governs the migratory behavior of T cell subsets. They also challenge previous models of the role of S1P in lymphocyte recirculation and suggest that S1P promotes retention of memory T cell subsets in secondary lymphoid organs, via S1PR2. Copyright © 2018 by The American Association of Immunologists, Inc.

  9. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire.

    Science.gov (United States)

    Le Gouill, Steven; Milpied, Noel; Buzyn, Agnès; De Latour, Régis Peffault; Vernant, Jean-Paul; Mohty, Mohamad; Moles, Marie-Pierre; Bouabdallah, Krimo; Bulabois, Claude-Eric; Dupuis, Jehan; Rio, Bernard; Gratecos, Nicole; Yakoub-Agha, Ibrahim; Attal, Michel; Tournilhac, Olivier; Decaudin, Didier; Bourhis, Jean-Henry; Blaise, Didier; Volteau, Christelle; Michallet, Mauricette

    2008-05-10

    Aggressive T-cell lymphomas (ATCLs) represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults. ATCLs show a worse prognosis than B-cell lymphomas. On behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire, we conducted a retrospective analysis including 77 ATCL patients who underwent allogeneic stem-cell transplantation (alloSCT). The different diagnosis included anaplastic large-cell lymphoma (ALCL; n = 27), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n = 27), angioimmunoblastic T-cell lymphoma (AITL; n = 11), hepatosplenic gamma/delta lymphoma (HSL; n = 3), T-cell granular lymphocytic leukemia (T-GLL; n = 1), nasal natural killer (NK)/T-cell lymphoma (nasal-NK/L; n = 3) or non-nasal NK/T-cell lymphoma (non-nasal-NK/L; n = 2), enteropathy-type T-cell (n = 1), and human T-lymphotropic virus (HTLV)-1 lymphoma (n = 2). Fifty-seven patients received a myeloablative conditioning regimen. Donors were human leukocyte antigen (HLA)-matched in 70 cases and related in 60 cases. Thirty-one patients were in complete remission (CR) at the time of alloSCT, whereas 26 were in partial response (PR). Five-year toxicity-related mortality (TRM) incidence was 33% (95% CI, 24% to 46%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57% (95% CI, 45% to 68%) and 53% (95% CI, 41% to 64%), respectively. In multivariate analysis, chemoresistant disease (stable, refractory, or progressing disease) at the time of alloSCT and the occurrence of severe grade 3 to 4 acute graft-versus-host disease (aGVHD) were the strongest adverse prognostic factors for OS (P = .03 and .03, respectively). Disease status at transplantation significantly influenced the 5-year EFS (P = .003), and an HLA-mismatched donor increased TRM (P = .04). We conclude that alloSCT is a potentially efficient therapy for NK/T lymphomas and is worth further investigation through prospective clinical trials.

  10. REGULATORY T CELLS AND VASECTOMY

    Science.gov (United States)

    Rival, Claudia; Wheeler, Karen; Jeffrey, Sarah; Qiao, Hui; Luu, Brian; Tewalt, Eric F; Engelhard, Victor H; Tardif, Stephen; Hardy, Daniel; del Rio, Roxana; Teuscher, Cory; Tung, Kenneth

    2013-01-01

    CD4+CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24 hours of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12–16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at seven months, the antibody titers fluctuated over time, suggesting a dynamic “balance” between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance. PMID:24080233

  11. Genetically modified T cells in cancer therapy: opportunities and challenges

    Science.gov (United States)

    Sharpe, Michaela; Mount, Natalie

    2015-01-01

    Tumours use many strategies to evade the host immune response, including downregulation or weak immunogenicity of target antigens and creation of an immune-suppressive tumour environment. T cells play a key role in cell-mediated immunity and, recently, strategies to genetically modify T cells either through altering the specificity of the T cell receptor (TCR) or through introducing antibody-like recognition in chimeric antigen receptors (CARs) have made substantial advances. The potential of these approaches has been demonstrated in particular by the successful use of genetically modified T cells to treat B cell haematological malignancies in clinical trials. This clinical success is reflected in the growing number of strategic partnerships in this area that have attracted a high level of investment and involve large pharmaceutical organisations. Although our understanding of the factors that influence the safety and efficacy of these therapies has increased, challenges for bringing genetically modified T-cell immunotherapy to many patients with different tumour types remain. These challenges range from the selection of antigen targets and dealing with regulatory and safety issues to successfully navigating the routes to commercial development. However, the encouraging clinical data, the progress in the scientific understanding of tumour immunology and the improvements in the manufacture of cell products are all advancing the clinical translation of these important cellular immunotherapies. PMID:26035842

  12. Genetically modified T cells in cancer therapy: opportunities and challenges

    Directory of Open Access Journals (Sweden)

    Michaela Sharpe

    2015-04-01

    Full Text Available Tumours use many strategies to evade the host immune response, including downregulation or weak immunogenicity of target antigens and creation of an immune-suppressive tumour environment. T cells play a key role in cell-mediated immunity and, recently, strategies to genetically modify T cells either through altering the specificity of the T cell receptor (TCR or through introducing antibody-like recognition in chimeric antigen receptors (CARs have made substantial advances. The potential of these approaches has been demonstrated in particular by the successful use of genetically modified T cells to treat B cell haematological malignancies in clinical trials. This clinical success is reflected in the growing number of strategic partnerships in this area that have attracted a high level of investment and involve large pharmaceutical organisations. Although our understanding of the factors that influence the safety and efficacy of these therapies has increased, challenges for bringing genetically modified T-cell immunotherapy to many patients with different tumour types remain. These challenges range from the selection of antigen targets and dealing with regulatory and safety issues to successfully navigating the routes to commercial development. However, the encouraging clinical data, the progress in the scientific understanding of tumour immunology and the improvements in the manufacture of cell products are all advancing the clinical translation of these important cellular immunotherapies.

  13. The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses

    Science.gov (United States)

    Khan, Shaniya H.; Martin, Matthew D.; Starbeck-Miller, Gabriel R.; Xue, Hai-Hui; Harty, John T.; Badovinac, Vladimir P.

    2015-01-01

    Abstract Memory CD8 T cells provide protection to immune hosts by eliminating pathogen-infected cells during re-infection. While parameters influencing the generation of primary (1°) CD8 T cells are well established, the factors controlling the development of secondary (2°) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2° memory (M) CD8 T cells. We observed that the time at which 1° M CD8 T cells enter into immune response impacts their fate and differentiation into 2° M CD8 T cells. Late-entry of 1° M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2° effector CD8 T cells, but also influenced the ability of 2° M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1° M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2° effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2° CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of Ag-driven 2° CD8 T cell responses. Thus, our data suggest that the process of 1° M to 2° M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches. PMID:26431533

  14. Malignant clinical features of anaplastic gliomas without IDH mutation.

    Science.gov (United States)

    Shibahara, Ichiyo; Sonoda, Yukihiko; Shoji, Takuhiro; Kanamori, Masayuki; Saito, Ryuta; Inoue, Tomoo; Kawaguchi, Tomohiro; Yamashita, Yoji; Watanabe, Takashi; Kumabe, Toshihiro; Watanabe, Mika; Suzuki, Hiroyoshi; Tominaga, Teiji

    2015-01-01

    Diagnosis of WHO grade III anaplastic gliomas does not always correspond to its clinical outcome because of the isocitrate dehydrogenase (IDH) gene status. Anaplastic gliomas without IDH mutation result in a poor prognosis, similar to grade IV glioblastomas. However, the malignant features of anaplastic gliomas without IDH mutation are not well understood. The aim of this study was to examine anaplastic gliomas, in particular those without IDH mutation, with regard to their malignant features, recurrence patterns, and association with glioma stem cells. We retrospectively analyzed 86 cases of WHO grade III anaplastic gliomas. Data regarding patient characteristics, recurrence pattern, and prognosis were obtained from medical records. We examined molecular alterations such as IDH mutation, 1p19q loss, TP53 mutation, MGMT promoter methylation, Ki67 labeling index, and CD133, SOX2, and NESTIN expression. Of the 86 patients with anaplastic gliomas, 58 carried IDH mutation, and 40 experienced recurrence. The first recurrence was local in 25 patients and distant in 15. Patients without IDH mutation exhibited significantly higher CD133 and SOX2 expression (P = .025 and .020, respectively) and more frequent distant recurrence than those with IDH mutation (P = .022). Patients with anaplastic gliomas without IDH mutation experienced distant recurrence and exhibited glioma stem cell markers, indicating that this subset may share some malignant characteristics with glioblastomas. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Therapy of solid cancers using T cells and running shoes

    DEFF Research Database (Denmark)

    Straten, Per Thor

    2017-01-01

    of tumor specific T cells at the tumor site, and underscores the need to define ways as how to increase immune cell infiltration to the tumor site. Regular exercise reduces the risk of cancer and disease recurrence, by largely unknown mechanisms. We recently demonstrated that voluntary wheel running showed...

  16. Cloning the interleukin 1 receptor from human T cells

    International Nuclear Information System (INIS)

    Sims, J.E.; Acres, R.B.; Grubin, C.E.; McMahan, C.J.; Wignall, J.M.; March, C.J.; Dower, S.K.

    1989-01-01

    cDNA clones of the interleukin 1 (IL-1) receptor expressed in a human T-cell clone have been isolated by using a murine IL-1 receptor cDNA as a probe. The human and mouse receptors show a high degree of sequence conservation. Both are integral membrane proteins possessing a single membrane-spanning segment. Similar to the mouse receptor, the human IL-1 receptor contains a large cytoplasmic region and an extracellular, IL-1 binding portion composed of three immunoglobulin-like domains. When transfected into COS cells, the human IL-1 receptor cDNA clone leads to expression of two different affinity classes of receptors, with K a values indistinguishable from those determined for IL-1 receptors in the original T-cell clone. An IL-1 receptor expressed in human dermal fibroblasts has also been cloned and sequenced and found to be identical to the IL-1 receptor expressed in T cells

  17. Human thymus regeneration and T cell reconstitution

    NARCIS (Netherlands)

    Legrand, Nicolas; Dontje, Wendy; van Lent, Anja U.; Spits, Hergen; Blom, Bianca

    2007-01-01

    The thymus supports the development of T cells throughout life from hematopoietic progenitor cells migrating from the bone marrow. During the early years after birth thymic activity is highest, but progressively declines resulting in diminished naïve T cell output. Underlying causes of thymic

  18. Surviving the crash: T-cell homeostasis

    Indian Academy of Sciences (India)

    TOSHIBA

    Spatial and temporal elements. – Cellular sites for the integration of cell death and survival cues. – Spatial regulation of Notch activity for cell survival. Page 4. Cell survival is determined by the availability and uptake of nutrients live dead. Activated T-cells. T-cells. Page 5. dead wildtype. Bax active -6A7. Nucleus – H33342.

  19. Targetless T cells in cancer immunotherapy

    DEFF Research Database (Denmark)

    thor Straten, Eivind Per; Garrido, Federico

    2016-01-01

    Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell ...

  20. Carbohydrates and T cells: A sweet twosome

    Science.gov (United States)

    Avci, Fikri Y.; Li, Xiangming; Tsuji, Moriya; Kasper, Dennis L.

    2013-01-01

    Carbohydrates as T cell-activating antigens have been generating significant interest. For many years, carbohydrates were thought of as T-independent antigens, however, more recent research had demonstrated that mono- or oligosaccharides glycosidically-linked to peptides can be recognized by T cells. T cell recognition of these glycopeptides depends on the structure of both peptide and glycan portions of the antigen. Subsequently, it was discovered that natural killer T cells recognized glycolipids when presented by the antigen presenting molecule CD1d. A transformative insight into glycan-recognition by T cells occurred when zwitterionic polysaccharides were discovered to bind to and be presented by MHCII to CD4+ T cells. Based on this latter observation, the role that carbohydrate epitopes generated from glycoconjugate vaccines had in activating helper T cells was explored and it was found that these epitopes are presented to specific carbohydrate recognizing T cells through a unique mechanism. Here we review the key interactions between carbohydrate antigens and the adaptive immune system at the molecular, cellular and systems levels exploring the significant biological implications in health and disease. PMID:23757291

  1. Regulation of T cell responses in atherosclerosis

    NARCIS (Netherlands)

    Puijvelde, Gijsbrecht Henricus Maria van

    2007-01-01

    One of the most important characteristics of atherosclerosis is the chronic inflammatory response in which T cells and NKT cells are very important. In this thesis several methods to modulate the activity of these T and NKT cells in atherosclerosis are described. The induction of regulatory T cells

  2. T cell immunosurveillance controls B lymphoma development

    OpenAIRE

    Kallies, Axel

    2014-01-01

    We recently showed a critical role for T cells in the immunosurveillance of nascent B cell lymphomas arising from mutations impacting plasma cell differentiation. Our data suggest that CD8+ T cells continuously eliminate mutated B cells that fail to downregulate their co-stimulatory machinery and the Fas death receptor, thus constraining B lymphoma pathogenesis.

  3. A gut-homing, oligoclonal CD4+ T cell population in severe-combined immunodeficient mice expressing a rearranged, transgenic class I-restricted alpha beta T cell receptor

    DEFF Research Database (Denmark)

    Reimann, J; Rudolphi, A; Spiess, S

    1995-01-01

    We studied the peripheral T cell compartment of H-2b severe combined immunodeficient (scid) mice that express a transgenic (tg) alpha beta T cell receptor (TcR) specific for the H-Y (male) epitope presented by the H-2 class I Db molecule. Large populations of CD3+ NK1.1-TCR beta T+ T cells were p...

  4. Targeting regulatory T cells in cancer.

    LENUS (Irish Health Repository)

    Byrne, William L

    2012-01-31

    Infiltration of tumors by regulatory T cells confers growth and metastatic advantages by inhibiting antitumor immunity and by production of receptor activator of NF-kappaB (RANK) ligand, which may directly stimulate metastatic propagation of RANK-expressing cancer cells. Modulation of regulatory T cells can enhance the efficacy of cancer immunotherapy. Strategies include depletion, interference with function, inhibition of tumoral migration, and exploitation of T-cell plasticity. Problems with these strategies include a lack of specificity, resulting in depletion of antitumor effector T cells or global interruption of regulatory T cells, which may predispose to autoimmune diseases. Emerging technologies, such as RNA interference and tetramer-based targeting, may have the potential to improve selectivity and efficacy.

  5. CMV-specific T cell therapy.

    Science.gov (United States)

    Einsele, Hermann; Kapp, Markus; Grigoleit, Götz Ulrich

    2008-01-01

    Human cytomegalovirus (CMV) infection continues to be one of the most important and life threatening complications after allogeneic stem cell transplantation (SCT). The reconstitution of CMV-specific T cell responses after SCT has been demonstrated to be protective against the development of CMV disease. To improve T cell immunity against CMV in bone marrow transplant patients, different strategies were explored. On one hand, CMV-specific T cells can be selected from the donor, and can be transferred to the patient without any further in vitro expansion. On the other hand, CMV-specific T cells can be activated and expanded in vitro by stimulation with antigen presenting cells (APCs) loaded with specific proteins or peptides. Here, we review the therapeutic application of CMV-specific T cells to fight CMV infection.

  6. Amino acid similarity accounts for T cell cross-reactivity and for "holes" in the T cell repertoire

    DEFF Research Database (Denmark)

    Pletscher-Frankild, Sune; de Boer, Rob J.; Lund, Ole

    2008-01-01

    Background: Cytotoxic T cell (CTL) cross-reactivity is believed to play a pivotal role in generating immune responses but the extent and mechanisms of CTL cross-reactivity remain largely unknown. Several studies suggest that CTL clones can recognize highly diverse peptides, some sharing no obvious...... sequence identity. The emerging realization in the field is that T cell receptors (TcR) recognize multiple distinct ligands. Principal Findings: First, we analyzed peptide scans of the HIV epitope SLFNTVATL (SFL9) and found that TCR specificity is position dependent and that biochemically similar amino...... to demonstrate that seemingly distinct T cell epitopes, i.e., ones with low sequence identity, are in fact more biochemically similar than expected. Additionally, an analysis of HIV immunogenicity data with our model showed that CTLs have the tendency to respond mostly to peptides that do not resemble self...

  7. Anaplastic Medullary Ependymoma Presenting as Subarachnoid Hemorrhage

    Directory of Open Access Journals (Sweden)

    Nicolas Nicastro

    2013-01-01

    Full Text Available A-41-year old man presented with violent thunderclap headache and a bilateral proprioceptive sensibility deficit of the upper limbs. Cerebral CT scan and MRI were negative. Lumbar puncture confirmed subarachnoid hemorrhage (SAH, but cerebral angiography was negative. Three months later, the patient presented with paraparesis, and a thorough work-up revealed a diffuse, anaplastic extramedullary C7-D10 ependymoma with meningeal carcinomatosis considered the source of hemorrhage. The patient went through a D5-D8 laminectomy, temozolomide chemotherapy, and radiotherapy. The situation remained stable for a few months. In this paper, we would like to emphasize that spinal masses should be considered in cases of SAH with negative diagnostic findings for aneurysms or arteriovenous malformation.

  8. Cytotoxic reactivity of gut lamina propria CD4+ alpha beta T cells in SCID mice with colitis

    DEFF Research Database (Denmark)

    Bonhagen, K; Thoma, S; Bland, P

    1996-01-01

    Polyclonal, mucosa-seeking memory/effector CD4+ T cells containing a large fraction of blasts activated in situ accumulate in the gut lamina propria of severe-combined immunodeficient (SCID) mice developing colitis after CD4+ T cell transplantation. CD4+ T cells isolated from different repopulated...

  9. T Cell Repertoire and Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Kenneth Croitoru

    1996-01-01

    Full Text Available The diversity of the T cell receptor repertoire is generated through rearrangement of the variable, junctional and constant region genes. Selection processes in the thymus and periphery serve to eliminate self-reacting T cells, thereby preventing autoimmune disease. The possibility that inflammatory bowel disease (IBD is an autoimmune disease has led to the search for an auto-antigen. In addition, studies are exploring the T cell receptor repertoire in IBD patients for changes that may provide clues regarding etiopathogenesis. Using monoclonal antibodies to T cell receptor variable-gene products or polymerase chain reaction analysis of variable-gene mRNA expression, the mucosal T cell repertoire has been examined in humans. The intestinal intraepithelial lymphocytes show a significant degree of oligoclonal expansion that may represent local antigen exposure or unique selection processes. This is in keeping with studies that show that murine intestinal intraepithelial lymphocytes undergo positive and possibly negative selection independent of the thymus. In the inflamed human gut, shifts in the T cell receptor repertoire may also reflect recruitment of peripheral T cells to the gut. In one study, a subset of Crohn’s disease patients was shown to have an increase in the proportion of variable β8 peripheral blood lymphocyte and mesenteric lymph node cells, suggesting a superantigen effect. The authors hypothesized that changes in the functional T cell receptor repertoire can also occur which might be independent of changes in the distribution of T cells expressing variable β T cell receptors. In fact, the authors have shown there is a selective decrease in the cytotoxic function of peripheral variable β8 T cells in Crohn’s disease. Furthermore, stimulation with the variable β8 selective bacterial enterotoxin staphylococcal enterotoxin E failed to increase the cytotoxic function in this subset of Crohn’s disease patients compared with

  10. Disabled-2 is a FOXP3 target gene required for regulatory T cell function

    OpenAIRE

    Jain, N; Nguyen, H; Friedline, RH; Malhotra, N; Brehm, M; Koyonagi, M; Bix, M; Cooper, JA; Chambers, CA; Kang, J

    2009-01-01

    FOXP3 expressing regulatory T cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. Here we show that in mouse peripheral lymphocytes, the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFβ responses, is exclusively expressed in FOXP3+ regulatory T cells. Dab2 is a direct target of FOXP3 and regulatory T cells lacking DAB2 are fun...

  11. Potential use of [gammadelta] T cell-based vaccines in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Mohd Wajid A. Khan

    2014-10-01

    Full Text Available Immunotherapy is a fast advancing methodology involving one of two approaches: 1 compounds targeting immune checkpoints, and 2 cellular immunomodulators. The latter approach is still largely experimental and features in vitro generated, live immune effector cells or antigen-presenting cells (APC. [gammadelta] T cells are known for their efficient in vitro tumor killing activities. Consequently, many laboratories worldwide are currently testing the tumor killing function of [gammadelta] T cells in clinical trials. Reported benefits are modest; however, these studies have demonstrated that large [gammadelta] T cell infusions were well tolerated. Here, we discuss the potential of using human [gammadelta] T cells not as effector cells but as a novel cellular vaccine for treatment of cancer patients. Antigen-presenting [gammadelta] T cells do not require to home to tumor tissues but, instead, need to interact with endogenous, tumor-specific [alphabeta] T cells in secondary lymphoid tissues. Newly mobilised effector [alphabeta] T cells are then thought to overcome the immune blockade by creating proinflammatory conditions fit for effector T cell homing to and killing of tumor cells. Immunotherapy may include tumor antigen-loaded [gammadelta] T cells alone or in combination with immune checkpoint inhibitors.

  12. A logical model provides insights into T cell receptor signaling.

    Directory of Open Access Journals (Sweden)

    Julio Saez-Rodriguez

    2007-08-01

    Full Text Available Cellular decisions are determined by complex molecular interaction networks. Large-scale signaling networks are currently being reconstructed, but the kinetic parameters and quantitative data that would allow for dynamic modeling are still scarce. Therefore, computational studies based upon the structure of these networks are of great interest. Here, a methodology relying on a logical formalism is applied to the functional analysis of the complex signaling network governing the activation of T cells via the T cell receptor, the CD4/CD8 co-receptors, and the accessory signaling receptor CD28. Our large-scale Boolean model, which comprises 94 nodes and 123 interactions and is based upon well-established qualitative knowledge from primary T cells, reveals important structural features (e.g., feedback loops and network-wide dependencies and recapitulates the global behavior of this network for an array of published data on T cell activation in wild-type and knock-out conditions. More importantly, the model predicted unexpected signaling events after antibody-mediated perturbation of CD28 and after genetic knockout of the kinase Fyn that were subsequently experimentally validated. Finally, we show that the logical model reveals key elements and potential failure modes in network functioning and provides candidates for missing links. In summary, our large-scale logical model for T cell activation proved to be a promising in silico tool, and it inspires immunologists to ask new questions. We think that it holds valuable potential in foreseeing the effects of drugs and network modifications.

  13. Immunoregulatory T Cells May Be Involved in Preserving CD4 T Cell Counts in HIV-Infected Long-Term Nonprogressors and Controllers

    DEFF Research Database (Denmark)

    Gaardbo, Julie C; Ronit, Andreas; Hartling, Hans J

    2014-01-01

    BACKGROUND: HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-term nonprogressors (LTNPs) also maintain normal CD4 T cell counts but have ongoing viral replication. We hypothesized that immunoregulatory mechanisms are involved in preserved CD4 T cell c...... of patients and controls. However, both ECs and LTNPs displayed a large proportion of activated Tregs suggesting immunoregulatory mechanisms to be involved in preserving CD4 T cell counts in HIV-infected nonprogressors.......BACKGROUND: HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-term nonprogressors (LTNPs) also maintain normal CD4 T cell counts but have ongoing viral replication. We hypothesized that immunoregulatory mechanisms are involved in preserved CD4 T cell...... counts in controllers and in LTNPs. METHODS: Twenty HIV-infected viremic controllers, 5 elite controllers (ECs), and 14 LTNPs were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Regulatory T cells (Tregs), Treg subpopulations, CD161+Th17...

  14. Surviving the crash: T-cell homeostasis

    Indian Academy of Sciences (India)

    TOSHIBA

    The formation of higher order apoptotic structures at the mitochondrion precedes cellular collapse dead. Tracking bax multimerization at mitochondria wildtype. Bax active -6A7. Nucleus – H33342. Apoptotic T-cells ...

  15. Dopamine, T cells and multiple sclerosis (MS).

    Science.gov (United States)

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-05-01

    Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R-D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient's Teffs to dopamine. DR agonists and antagonists confer some benefits in

  16. Mechanical regulation of T-cell functions

    OpenAIRE

    Chen, Wei; Zhu, Cheng

    2013-01-01

    T cells are key players of the mammalian adaptive immune system. They experience different mechanical microenvironments during their life cycles, from the thymus, secondary lymph organs, and peripheral tissues that are free of externally applied force but display variable substrate rigidities, to the blood and lymphatic circulation systems where complicated hydrodynamic forces are present. Regardless of whether T cells are subject to external forces or generate their own internal forces, they...

  17. Understanding and Exploiting the T - Cell Memory

    Directory of Open Access Journals (Sweden)

    Kshipra Chandrashekhar1

    Full Text Available Immunological memory is one of the lesser understood aspects of adaptive immunity which protects organisms from recurrent and persistent attack by pathogens. The central event in the generation of both humoral and cell mediated immune responses is the activation and clonal expansion of T cells. T cell activation is initiated by interaction of the TCR-CD3 complex with processed antigenic peptide bound to either a class I (CD8+cells or class II (CD 4+cells MHC molecule on the surface of antigen presenting cell (APC. On interaction of a naïve T cell with the processed antigen initiates a cascade of events which activates the resting T cell to enter the cell cycle, proliferating and developing into a clone of progeny cells, which differentiate into memory or effector T cells. Memory T cells are generated by antigen interaction and remain long but quiescent in nature, however responding with greater reactivity to a subsequent challenge with the same antigen, generating a secondary response. Memory cells, though in the G0 stage of the cell cycle require a lower level of activation than so naïve cells. A lot of work in this direction can yield a whole lot of interesting findings which will help us develop better vaccines for chronic animal diseases like Tuberculosis, Johne’s disease using suitable animal models. A better understanding of these issues may lead to improvements in the design of vaccines which can be used to generate potent protective T cell memory against pathogens. In the present article various properties of memory T cells along with their implications to vaccine development have been reviewed. [Veterinary World 2010; 3(7.000: 343-345

  18. T cell activation in APECED patients

    OpenAIRE

    Mannerström, Helga

    2013-01-01

    Autoimmune polyendocrinopathy-candidasis-ectodermal dystrophy, APECED, is a rare monogenic autoimmune disease in humans, which is caused by loss-of-function mutation in Autoimmune Regulator gene, AIRE. Previous results have shown impairments in the circulating T cells of the APECED patients. In this study we wanted to look closer on the disturbance in the T cell receptor development of APECED patients. By studying the TCR-mediated responsiveness of CD3 stimulation and comparing the activation...

  19. Induction and analysis of antigen-specific T cell responses in melanoma patients and animal models

    NARCIS (Netherlands)

    Bins, Adriaan Dirk

    2007-01-01

    This thesis introduces a novel T cell vaccination method that uses a tattoo machine to inject DNA in the skin of the vaccinee. In comparison to other experimental vaccination methods DNA tattooing is very strong: besides small laboratory animals also large animals mount strong T cell responses upon

  20. IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis

    DEFF Research Database (Denmark)

    Luda, Katarzyna M.; Joeris, Thorsten; Persson, Emma K.

    2016-01-01

    The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence...... dependent DCs in the maintenance of intestinal T cell homeostasis....

  1. CD4+ T cell effects on CD8+ T cell location defined using bioluminescence.

    Directory of Open Access Journals (Sweden)

    Mitra Azadniv

    2011-01-01

    Full Text Available T lymphocytes of the CD8+ class are critical in delivering cytotoxic function and in controlling viral and intracellular infections. These cells are "helped" by T lymphocytes of the CD4+ class, which facilitate their activation, clonal expansion, full differentiation and the persistence of memory. In this study we investigated the impact of CD4+ T cells on the location of CD8+ T cells, using antibody-mediated CD4+ T cell depletion and imaging the antigen-driven redistribution of bioluminescent CD8+ T cells in living mice. We documented that CD4+ T cells influence the biodistribution of CD8+ T cells, favoring their localization to abdominal lymph nodes. Flow cytometric analysis revealed that this was associated with an increase in the expression of specific integrins. The presence of CD4+ T cells at the time of initial CD8+ T cell activation also influences their biodistribution in the memory phase. Based on these results, we propose the model that one of the functions of CD4+ T cell "help" is to program the homing potential of CD8+ T cells.

  2. Neurohypophysial Receptor Gene Expression by Thymic T Cell Subsets and Thymic T Cell Lymphoma Cell Lines

    Directory of Open Access Journals (Sweden)

    I. Hansenne

    2004-01-01

    transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes, OTR, V1R, V2R and V3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while V3R transcription is restricted to CD4+ CD8+ and CD8+ thymic cells. Neither V1R nor V2R transcripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the restriction of OTR transcription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment.

  3. Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation.

    Science.gov (United States)

    Liang, Wei; Mao, Shanshan; Sun, Shijie; Li, Ming; Li, Zhi; Yu, Rui; Ma, Tonghui; Gu, Jianguo; Zhang, Jianing; Taniguchi, Naoyuki; Li, Wenzhe

    2018-01-01

    CD4 + T cell activation promotes the pathogenic process of systemic lupus erythematosus (SLE). T cell receptor (TCR) complex are highly core fucosylated glycoproteins, which play important roles in T cell activation. In this study, we found that the core fucosylation of CD4 + T cells was significantly increased in SLE patients. Loss of core fucosyltransferase (Fut8), the sole enzyme for catalyzing the core fucosylation of N-glycan, significantly reduced CD4 + T cell activation and ameliorated the experimental autoimmune encephalomyelitis-induced syndrome in Fut8 -/- mice. T cell activation with OVA 323-339 loaded major histocompatibility complex II (pMHC-II) on B cell was dramatically attenuated in Fut8 -/- OT-II CD4 + T cells compared with Fut8 +/+ OT-II CD4 + T cells. Moreover, the phosphorylation of ZAP-70 was significantly reduced in Fut8 +/+ OT-II CD4 + T cells by the treatment of fucosidase. Our results suggest that core fucosylation is required for efficient TCR-pMHC-II contacts in CD4 + T cell activation, and hyper core fucosylation may serve as a potential novel biomarker in the sera from SLE patients.

  4. Memory CD4 T cells in influenza.

    Science.gov (United States)

    Zens, Kyra D; Farber, Donna L

    2015-01-01

    Influenza A virus is a significant cause of morbidity and mortality worldwide, particularly among young children and the elderly. Current vaccines induce neutralizing antibody responses directed toward highly variable viral surface proteins, resulting in limited heterosubtypic protection to new viral serotypes. By contrast, memory CD4 T cells recognize conserved viral proteins and are cross-reactive to multiple influenza strains. In humans, virus-specific memory CD4 T cells were found to be the protective correlate in human influenza challenge studies, suggesting their key role in protective immunity. In mouse models, memory CD4 T cells can mediate protective responses to secondary influenza infection independent of B cells or CD8 T cells, and can influence innate immune responses. Importantly, a newly defined, tissue-resident CD4 memory population has been demonstrated to be retained in lung tissue and promote optimal protective responses to an influenza infection. Here, we review the current state of results regarding the generation of memory CD4 T cells following primary influenza infection, mechanisms for their enhanced efficacy in protection from secondary challenge including their phenotype, localization, and function in the context of both mouse models and human infection. We also discuss the generation of memory CD4 T cells in response to influenza vaccines and its future implications for vaccinology.

  5. Malaria drives T cells to exhaustion

    Directory of Open Access Journals (Sweden)

    Michelle N Wykes

    2014-05-01

    Full Text Available Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp.. Recent research on malaria, has investigated the Programmed cell death-1 (PD-1 pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4+ T cells and an unappreciated role for CD8+ T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8+ T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria.

  6. Identifying specificity groups in the T cell receptor repertoire.

    Science.gov (United States)

    Glanville, Jacob; Huang, Huang; Nau, Allison; Hatton, Olivia; Wagar, Lisa E; Rubelt, Florian; Ji, Xuhuai; Han, Arnold; Krams, Sheri M; Pettus, Christina; Haas, Nikhil; Arlehamn, Cecilia S Lindestam; Sette, Alessandro; Boyd, Scott D; Scriba, Thomas J; Martinez, Olivia M; Davis, Mark M

    2017-07-06

    T cell receptor (TCR) sequences are very diverse, with many more possible sequence combinations than T cells in any one individual. Here we define the minimal requirements for TCR antigen specificity, through an analysis of TCR sequences using a panel of peptide and major histocompatibility complex (pMHC)-tetramer-sorted cells and structural data. From this analysis we developed an algorithm that we term GLIPH (grouping of lymphocyte interactions by paratope hotspots) to cluster TCRs with a high probability of sharing specificity owing to both conserved motifs and global similarity of complementarity-determining region 3 (CDR3) sequences. We show that GLIPH can reliably group TCRs of common specificity from different donors, and that conserved CDR3 motifs help to define the TCR clusters that are often contact points with the antigenic peptides. As an independent validation, we analysed 5,711 TCRβ chain sequences from reactive CD4 T cells from 22 individuals with latent Mycobacterium tuberculosis infection. We found 141 TCR specificity groups, including 16 distinct groups containing TCRs from multiple individuals. These TCR groups typically shared HLA alleles, allowing prediction of the likely HLA restriction, and a large number of M. tuberculosis T cell epitopes enabled us to identify pMHC ligands for all five of the groups tested. Mutagenesis and de novo TCR design confirmed that the GLIPH-identified motifs were critical and sufficient for shared-antigen recognition. Thus the GLIPH algorithm can analyse large numbers of TCR sequences and define TCR specificity groups shared by TCRs and individuals, which should greatly accelerate the analysis of T cell responses and expedite the identification of specific ligands.

  7. FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.

    Directory of Open Access Journals (Sweden)

    Jeremy A Sullivan

    2012-02-01

    Full Text Available CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory is incomplete. The PI3K/Akt signaling pathway controls cell growth in many cell types by modulating the activity of FOXO transcription factors. But the role of FOXOs in regulating CD8 T cell memory remains unknown. We show that phosphorylation of Akt, FOXO and mTOR in CD8 T cells occurs in a dynamic fashion in vivo during an acute viral infection. To elucidate the potentially dynamic role for FOXO3 in regulating homeostasis of activated CD8 T cells in lymphoid and non-lymphoid organs, we infected global and T cell-specific FOXO3-deficient mice with Lymphocytic Choriomeningitis Virus (LCMV. We found that FOXO3 deficiency induced a marked increase in the expansion of effector CD8 T cells, preferentially in the spleen, by T cell-intrinsic mechanisms. Mechanistically, the enhanced accumulation of proliferating CD8 T cells in FOXO3-deficient mice was not attributed to an augmented rate of cell division, but instead was linked to a reduction in cellular apoptosis. These data suggested that FOXO3 might inhibit accumulation of growth factor-deprived proliferating CD8 T cells by reducing their viability. By virtue of greater accumulation of memory precursor effector cells during expansion, the numbers of memory CD8 T cells were strikingly increased in the spleens of both global and T cell-specific FOXO3-deficient mice. The augmented CD8 T cell memory was durable, and FOXO3 deficiency did not perturb any of the qualitative attributes of memory T cells. In summary, we have identified FOXO3 as a critical regulator of CD8 T cell memory, and therapeutic modulation of FOXO3 might enhance vaccine-induced protective immunity against intracellular pathogens.

  8. FOXO3 Regulates CD8 T Cell Memory by T Cell-Intrinsic Mechanisms

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    Sullivan, Jeremy A.; Kim, Eui Ho; Plisch, Erin H.; Peng, Stanford L.; Suresh, M.

    2012-01-01

    CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory is incomplete. The PI3K/Akt signaling pathway controls cell growth in many cell types by modulating the activity of FOXO transcription factors. But the role of FOXOs in regulating CD8 T cell memory remains unknown. We show that phosphorylation of Akt, FOXO and mTOR in CD8 T cells occurs in a dynamic fashion in vivo during an acute viral infection. To elucidate the potentially dynamic role for FOXO3 in regulating homeostasis of activated CD8 T cells in lymphoid and non-lymphoid organs, we infected global and T cell-specific FOXO3-deficient mice with Lymphocytic Choriomeningitis Virus (LCMV). We found that FOXO3 deficiency induced a marked increase in the expansion of effector CD8 T cells, preferentially in the spleen, by T cell-intrinsic mechanisms. Mechanistically, the enhanced accumulation of proliferating CD8 T cells in FOXO3-deficient mice was not attributed to an augmented rate of cell division, but instead was linked to a reduction in cellular apoptosis. These data suggested that FOXO3 might inhibit accumulation of growth factor-deprived proliferating CD8 T cells by reducing their viability. By virtue of greater accumulation of memory precursor effector cells during expansion, the numbers of memory CD8 T cells were strikingly increased in the spleens of both global and T cell-specific FOXO3-deficient mice. The augmented CD8 T cell memory was durable, and FOXO3 deficiency did not perturb any of the qualitative attributes of memory T cells. In summary, we have identified FOXO3 as a critical regulator of CD8 T cell memory, and therapeutic modulation of FOXO3 might enhance vaccine-induced protective immunity against intracellular pathogens. PMID:22359505

  9. Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells.

    Science.gov (United States)

    Huang, Szu-Han; Ren, Yanqin; Thomas, Allison S; Chan, Dora; Mueller, Stefanie; Ward, Adam R; Patel, Shabnum; Bollard, Catherine M; Cruz, Conrad Russell; Karandish, Sara; Truong, Ronald; Macedo, Amanda B; Bosque, Alberto; Kovacs, Colin; Benko, Erika; Piechocka-Trocha, Alicja; Wong, Hing; Jeng, Emily; Nixon, Douglas F; Ho, Ya-Chi; Siliciano, Robert F; Walker, Bruce D; Jones, R Brad

    2018-02-01

    The presence of persistent, latent HIV reservoirs in CD4+ T cells obstructs current efforts to cure infection. The so-called kick-and-kill paradigm proposes to purge these reservoirs by combining latency-reversing agents with immune effectors such as cytotoxic T lymphocytes. Support for this approach is largely based on success in latency models, which do not fully reflect the makeup of latent reservoirs in individuals on long-term antiretroviral therapy (ART). Recent studies have shown that CD8+ T cells have the potential to recognize defective proviruses, which comprise the vast majority of all infected cells, and that the proviral landscape can be shaped over time due to in vivo clonal expansion of infected CD4+ T cells. Here, we have shown that treating CD4+ T cells from ART-treated individuals with combinations of potent latency-reversing agents and autologous CD8+ T cells consistently reduced cell-associated HIV DNA, but failed to deplete replication-competent virus. These CD8+ T cells recognized and potently eliminated CD4+ T cells that were newly infected with autologous reservoir virus, ruling out a role for both immune escape and CD8+ T cell dysfunction. Thus, our results suggest that cells harboring replication-competent HIV possess an inherent resistance to CD8+ T cells that may need to be addressed to cure infection.

  10. T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System.

    Science.gov (United States)

    Huang, Wei-Chen; Easom, Nicholas J; Tang, Xin-Zi; Gill, Upkar S; Singh, Harsimran; Robertson, Francis; Chang, Chiwen; Trowsdale, John; Davidson, Brian R; Rosenberg, William M; Fusai, Giuseppe; Toubert, Antoine; Kennedy, Patrick T; Peppa, Dimitra; Maini, Mala K

    2017-02-01

    NK cells, which are highly enriched in the liver, are potent regulators of antiviral T cells and immunopathology in persistent viral infection. We investigated the role of the NKG2D axis in T cell/NK cell interactions in hepatitis B. Activated and hepatitis B virus (HBV)-specific T cells, particularly the CD4 fraction, expressed NKG2D ligands (NKG2DL), which were not found on T cells from healthy controls (p < 0.001). NKG2DL-expressing T cells were strikingly enriched within HBV-infected livers compared with the periphery or to healthy livers (p < 0.001). NKG2D + NK cells were also increased and preferentially activated in the HBV-infected liver (p < 0.001), in direct proportion to the percentage of MICA/B-expressing CD4 T cells colocated within freshly isolated liver tissue (p < 0.001). This suggests that NKG2DL induced on T cells within a diseased organ can calibrate NKG2D-dependent activation of local NK cells; furthermore, NKG2D blockade could rescue HBV-specific and MICA/B-expressing T cells from HBV-infected livers. To our knowledge, this is the first ex vivo demonstration that non-virally infected human T cells can express NKG2DL, with implications for stress surveillance by the large number of NKG2D-expressing NK cells sequestered in the liver. Copyright © 2017 The Authors.

  11. Prevotella intermedia Stimulates Expansion of Vβ-Specific CD4+ T Cells

    Science.gov (United States)

    Leung, K.-P.; Torres, Barbara A.

    2000-01-01

    Recent evidence suggests that certain periodontal pathogens preferentially stimulate T cells expressing specific variable regions on the β chain (Vβ) of the T-cell receptor, which may indicate the presence of a superantigen. Superantigens are microbial proteins that activate large numbers of CD4+ T cells in a Vβ-specific manner. The purpose of this study was to determine whether Prevotella intermedia, a putative periodontal pathogen, activates populations of specific Vβ on CD4+ T cells. Among the bacterial strains tested, P. intermedia strain 17, a clinical isolate, induced the strongest proliferative response in peripheral blood mononuclear cells. Antibodies raised against whole cells of this organism blocked the proliferative activity. P. intermedia-induced proliferation was T-cell specific and required the presence of antigen-presenting cells. Flow cytometric analysis showed that CD4+ T-cell subsets expressing Vβ8, Vβ12, and Vβ17 expanded in response to P. intermedia strain 17. The ability of P. intermedia to stimulate CD4+-T-cell proliferation was further supported by the production profiles of key T-cell cytokines, gamma interferon and interleukin-2. The data collectively suggest that certain strains of P. intermedia can activate Vβ-specific T cells in a manner similar to that of other known microbial superantigens. PMID:10948175

  12. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE

    DEFF Research Database (Denmark)

    Liu, Yawei; Teige, Ingrid; Birnir, Bryndis

    2006-01-01

    ) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between......Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS...... neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4...

  13. A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells.

    Science.gov (United States)

    Kamiya, Takahiro; Wong, Desmond; Png, Yi Tian; Campana, Dario

    2018-03-13

    Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression. In 25 experiments, median TCRαβ expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRαβ cell depletion yielded virtually pure TCRαβ-negative T cells. Anti-CD3ε PEBLs abrogated TCRαβ-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3ε PEBL-T cells, expression of an anti-CD19-41BB-CD3ζ CAR induced cytokine secretion, long-term proliferation, and CD19 + leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRαβ expression. In immunodeficient mice, anti-CD3ε PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRαβ expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies. © 2018 by The American Society of Hematology.

  14. T Cell factor 1 represses CD8+ effector T cell formation and function.

    Science.gov (United States)

    Tiemessen, Machteld M; Baert, Miranda R M; Kok, Lianne; van Eggermond, Marja C J A; van den Elsen, Peter J; Arens, Ramon; Staal, Frank J T

    2014-12-01

    The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8(+) T cells. However, its role in the initial phases of CD8(+) T effector cell formation has remained unexplored. We report that high levels of Wnt signaling and Tcf1 are operational in naive and memory CD8(+) T cells, whereas Wnt signaling and Tcf1 were low in effector CD8(+) T cells. CD8(+) T cells deficient in Tcf1 produce IFN-γ more rapidly, coinciding with increased demethylation of the IFN-γ enhancer and higher expression of the transcription factors Tbet and Blimp1. Moreover, virus-specific Tcf1(-/-) CD8(+) T cells show accelerated expansion in acute infection, which is associated with increased IFN-γ and TNF production and lower viral load. Genetic complementation experiments with various Tcf1 isoforms indicate that Tcf1 dosage and protein stability are critical in suppressing IFN-γ production. Isoforms lacking the β-catenin binding domain are equally effective in inhibiting CD8(+) effector T cell formation. Thus, Tcf1 functions as a repressor of CD8(+) effector T cell formation in a β-catenin/Wnt-independent manner. Copyright © 2014 by The American Association of Immunologists, Inc.

  15. Supernatural T cells: genetic modification of T cells for cancer therapy.

    Science.gov (United States)

    Kershaw, Michael H; Teng, Michele W L; Smyth, Mark J; Darcy, Phillip K

    2005-12-01

    Immunotherapy is receiving much attention as a means of treating cancer, but complete, durable responses remain rare for most malignancies. The natural immune system seems to have limitations and deficiencies that might affect its ability to control malignant disease. An alternative to relying on endogenous components in the immune repertoire is to generate lymphocytes with abilities that are greater than those of natural T cells, through genetic modification to produce 'supernatural' T cells. This Review describes how such T cells can circumvent many of the barriers that are inherent in the tumour microenvironment while optimizing T-cell specificity, activation, homing and antitumour function.

  16. Targetless T cells in cancer immunotherapy.

    Science.gov (United States)

    Thor Straten, Per; Garrido, Federico

    2016-01-01

    Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell transfer (ACT) using expanded tumor infiltrating lymphocytes (TIL) or genetically modified cytotoxic T cells. However, despite clear clinical responses, only a fraction of patients respond to treatment and there is an urgent call for characterization of predictive biomarkers. CD8 positive T cells can infiltrate tumor tissues and destroy HLA class I positive tumor cells expressing the specific antigen. In fact, current progress in the field of cancer immune therapy is based on the capacity of T cells to kill cancer cells that present tumor antigen in the context on an HLA class I molecule. However, it is also well established that cancer cells are often characterized by loss or down regulation of HLA class I molecules, documented in a variety of human tumors. Consequently, immune therapy building on CD8 T cells will be futile in patients harboring HLA class-I negative or deficient cancer cells. It is therefore mandatory to explore if these important molecules for T cell cytotoxicity are expressed by cancer target cells. We have indications that different types of immunotherapy can modify the tumor microenvironment and up-regulate reduced HLA class I expression in cancer cells but only if the associated molecular mechanisms is reversible (soft). However, in case of structural (hard) aberrations causing HLA class I loss, tumor cells will not be able to recover HLA class I expression and as a consequence will escape T-cell lysis and continue to growth. Characterization of the molecular mechanism underlying the lack or downregulation of HLA class I expression, seems to be a crucial step predicting clinical responses to T cell mediated immunotherapy, and possibly aid the

  17. T-cell-directed therapies in systemic lupus erythematosus.

    Science.gov (United States)

    Nandkumar, P; Furie, R

    2016-09-01

    Drug development for the treatment of systemic lupus erythematosus (SLE) has largely focused on B-cell therapies. A greater understanding of the immunopathogenesis of SLE coupled with advanced bioengineering has allowed for clinical trials centered on other targets for SLE therapy. The authors discuss the benefits and shortcomings of focusing on T-cell-directed therapies in SLE and lupus nephritis clinical trials. © The Author(s) 2016.

  18. Natural killer T cells in lipoprotein metabolism and atherosclerosis

    OpenAIRE

    Getz, Godfrey S; VanderLaan, Paul A; Reardon, Catherine A

    2011-01-01

    Cells of both the innate and adaptive immune system participate in the development of atherosclerosis, a chronic inflammatory disorder of medium and large arteries. Natural killer T (NKT) cells express surface markers characteristic of natural killer cells and conventional T cells and bridge the innate and adaptive immune systems. The development and activation of NKT cells is dependent upon CD1d, a MHC-class I-type molecule that presents lipids, especially glycolipids to the TCR on NKT cells...

  19. Markers of T Cell Senescence in Humans

    Directory of Open Access Journals (Sweden)

    Weili Xu

    2017-08-01

    Full Text Available Many countries are facing the aging of their population, and many more will face a similar obstacle in the near future, which could be a burden to many healthcare systems. Increased susceptibility to infections, cardiovascular and neurodegenerative disease, cancer as well as reduced efficacy of vaccination are important matters for researchers in the field of aging. As older adults show higher prevalence for a variety of diseases, this also implies higher risk of complications, including nosocomial infections, slower recovery and sequels that may reduce the autonomy and overall quality of life of older adults. The age-related effects on the immune system termed as “immunosenescence” can be exemplified by the reported hypo-responsiveness to influenza vaccination of the elderly. T cells, which belong to the adaptive arm of the immune system, have been extensively studied and the knowledge gathered enables a better understanding of how the immune system may be affected after acute/chronic infections and how this matters in the long run. In this review, we will focus on T cells and discuss the surface and molecular markers that are associated with T cell senescence. We will also look at the implications that senescent T cells could have on human health and diseases. Finally, we will discuss the benefits of having these markers for investigators and the future work that is needed to advance the field of T cell senescence markers.

  20. Regulatory T-cells and autoimmunity.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    Approximately 20% of the population is affected by autoimmune or inflammatory diseases mediated by an abnormal immune response. A characteristic feature of autoimmune disease is the selective targeting of a single cell type, organ or tissue by certain populations of autoreactive T-cells. Examples of such diseases include rheumatoid arthritis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus (SLE), all of which are characterized by chronic inflammation, tissue destruction and target organ malfunction. Although strong evidence links most autoimmune diseases to specific genes, considerable controversy prevails regarding the role of regulatory T-cell populations in the disease process. These cells are now also believed to play a key role in mediating transplantation tolerance and inhibiting the induction of tumor immunity. Though the concept of therapeutic immune regulation aimed at treating autoimmune pathology has been validated in many animal models, the development of strategies for the treatment of human autoimmune disorders remains in its infancy. The main obstacles to this include the conflicting findings of different model systems, as well as the contrasting functions of regulatory T-cells and cytokines involved in the development of such disorders. This review examines the role of regulatory T-cells in the pathogenesis of autoimmunity and describes the therapeutic potential of these cells for the prevention of immune-mediated pathologies in the future. Although much remains to be learned about such pathologies, a clearer understanding of the mechanisms by which regulatory T-cells function will undoubtedly lead to exciting new possibilities for immunotherapeutics.

  1. T cell recognition of breast cancer antigens

    DEFF Research Database (Denmark)

    Petersen, Nadia Viborg; Andersen, Sofie Ramskov; Andersen, Rikke Sick

    Recent studies are encouraging research of breast cancer immunogenicity to evaluate the applicability ofimmunotherapy as a treatment strategy. The epitope landscape in breast cancer is minimally described, thus it is necessary to identify T cell targets to develop immune mediated therapies.......This project investigates four proteins commonly upregulated in breast cancer and thus probable tumor associated antigens (TAAs). Aromatase, prolactin, NEK3, and PIAS3 contribute to increase growth, survival, and motility of malignant cells. Aspiring to uncover novel epitopes for cytotoxic T cells, a reverse...... recognition utilizing DNA barcode labeled MHC multimers to screen peripheral blood lymphocytes from breast cancer patients and healthy donor samples. Signif-icantly more TAA specific T cell responses were detected in breast cancer patients than healthy donors for both HLA-A*0201 (P

  2. T Cell exhaustion in protozoan disease

    Science.gov (United States)

    Gigley, Jason P.; Bhadra, Rajarshi; Moretto, Magali M.; Khan, Imtiaz A.

    2012-01-01

    Protozoan parasites cause severe morbidity and mortality in humans worldwide, especially in developing countries where access to chemotherapeutic agents is limited. Although parasites initially evoke a robust immune response, subsequent immunity fails to clear infection, ultimately leading to the chronic stage. This enigmatic situation was initially addressed in chronic viral models, where T cells lose their function, a phenomenon referred to as ’exhaustion‘. However, recent studies demonstrate that this paradigm can be extended to protozoan diseases as well, albeit with notable differences. These studies have revealed that T cell responses generated against Toxoplasma gondii, Plasmodium sp. and Leishmania sp. can become dysfunctional. This Review discusses T cell exhaustion in parasitic infection, mechanisms of development, and a possible role in disease outcome. PMID:22832368

  3. Tissue-resident memory T cells.

    Science.gov (United States)

    Shin, Haina; Iwasaki, Akiko

    2013-09-01

    Tissues such as the genital tract, skin, and lung act as barriers against invading pathogens. To protect the host, incoming microbes must be quickly and efficiently controlled by the immune system at the portal of entry. Memory is a hallmark of the adaptive immune system, which confers long-term protection and is the basis for efficacious vaccines. While the majority of existing vaccines rely on circulating antibody for protection, struggles to develop antibody-based vaccines against infections such as herpes simplex virus (HSV) and human immunodeficiency virus (HIV) have underscored the need to generate memory T cells for robust antiviral control. The circulating memory T-cell population is generally divided into two subsets: effector memory (TEM ) and central memory (TCM ). These two subsets can be distinguished by their localization, as TCM home to secondary lymphoid organs and TEM circulate through non-lymphoid tissues. More recently, studies have identified a third subset, called tissue-resident memory (TRM ) cells, based on its migratory properties. This subset is found in peripheral tissues that require expression of specific chemoattractants and homing receptors for T-cell recruitment and retention, including barrier sites such as the skin and genital tract. In this review, we categorize different tissues in the body based on patterns of memory T-cell migration and tissue residency. This review also describes the rules for TRM generation and the properties that distinguish them from circulating TEM and TCM cells. Finally, based on the failure of recent T-cell-based vaccines to provide optimal protection, we also discuss the potential role of TRM cells in vaccine design against microbes that invade through the peripheral tissues and highlight new vaccination strategies that take advantage of this newly described memory T-cell subset. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Pharmacologic suppression of target cell recognition by engineered T cells expressing chimeric T-cell receptors.

    Science.gov (United States)

    Alvarez-Vallina, L; Yañez, R; Blanco, B; Gil, M; Russell, S J

    2000-04-01

    Adoptive therapy with autologous T cells expressing chimeric T-cell receptors (chTCRs) is of potential interest for the treatment of malignancy. To limit possible T-cell-mediated damage to normal tissues that weakly express the targeted tumor antigen (Ag), we have tested a strategy for the suppression of target cell recognition by engineered T cells. Jurkat T cells were transduced with an anti-hapten chTCR tinder the control of a tetracycline-suppressible promoter and were shown to respond to Ag-positive (hapten-coated) but not to Ag-negative target cells. The engineered T cells were then reacted with hapten-coated target cells at different effector to target cell ratios before and after exposure to tetracycline. When the engineered T cells were treated with tetracycline, expression of the chTCR was greatly decreased and recognition of the hapten-coated target cells was completely suppressed. Tetracycline-mediated suppression of target cell recognition by engineered T cells may be a useful strategy to limit the toxicity of the approach to cancer gene therapy.

  5. Synthetic biology approaches to engineer T cells.

    Science.gov (United States)

    Wu, Chia-Yung; Rupp, Levi J; Roybal, Kole T; Lim, Wendell A

    2015-08-01

    There is rapidly growing interest in learning how to engineer immune cells, such as T lymphocytes, because of the potential of these engineered cells to be used for therapeutic applications such as the recognition and killing of cancer cells. At the same time, our knowhow and capability to logically engineer cellular behavior is growing rapidly with the development of synthetic biology. Here we describe how synthetic biology approaches are being used to rationally alter the behavior of T cells to optimize them for therapeutic functions. We also describe future developments that will be important in order to construct safe and precise T cell therapeutics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Peripheral T cell lymphoma: Not otherwise specified

    Directory of Open Access Journals (Sweden)

    Anusha H Pai

    2015-01-01

    Full Text Available Peripheral T cell lymphoma (PTCL is a heterogeneous group of hematological tumors originating from mature T cells, which constitutes less than 15% of all non-Hodgkins lymphomas in adults. Primary cutaneous PTCL-not otherwise specified (NOS represent a subgroup of PTCLs with no consistent immunophenotypic, genetic or clinical features. PTCL-NOS frequently has an aggressive course with a tendency for systemic involvement, however, a well-defined therapeutic and prognostic approach has not been outlined yet. We report a case of PTCL-NOS with multiple cutaneous lesions in a young adult male with an emphasis on the treatment modality used.

  7. Regulatory T Cell Immunity in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Hilman Zulkifli Amin

    2017-04-01

    Full Text Available Atherosclerosis is a chronic inflammatory disorder involving innate and adaptive immunity process. Effector T cell (Teff responses promote atherosclerotic disease, whereas regulatory T cells (Tregs have been shown to play a protective role against atherosclerosis by down-regulating inflammatory responses which include multiple mechanisms. Compelling experimental data suggest that shifting the Treg/Teff balance toward Tregs may be a possible therapeutic approach for atherosclerotic disease, although the role of Tregs in human atherosclerotic disease has not been fully elucidated. In this review, we discuss recent advances in our understanding of the roles of Tregs and Teffs in experimental atherosclerosis, as well as human coronary artery disease.

  8. CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

    Science.gov (United States)

    Sinha, Sushmita; Boyden, Alexander W.; Itani, Farah R.; Crawford, Michael P.; Karandikar, Nitin J.

    2015-01-01

    The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4+ T-cells as mediators and regulators of disease. Interestingly, CD8+ T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial. Several animal models and MS patient studies support a pathogenic role for CNS-specific CD8+ T-cells, whereas we and others have demonstrated a regulatory role for these cells in disease. In this review, we describe studies that have investigated the role of CD8+ T-cells in MS and EAE, presenting evidence for both pathogenic and regulatory functions. In our studies, we have shown that cytotoxic/suppressor CD8+ T-cells are CNS antigen-specific, MHC class I-restricted, IFNγ- and perforin-dependent, and are able to inhibit disease. The clinical relevance for CD8+ T-cell suppressive function is best described by a lack of their function during MS relapse, and importantly, restoration of their suppressive function during quiescence. Furthermore, CD8+ T-cells with immunosuppressive functions can be therapeutically induced in MS patients by glatiramer acetate (GA) treatment. Unlike CNS-specific CD8+ T-cells, these immunosuppressive GA-induced CD8+ T-cells appear to be HLA-E restricted. These studies have provided greater fundamental insight into the role of autoreactive as well as therapeutically induced CD8+ T-cells in disease amelioration. The clinical implications for these findings are immense and we propose that this natural process can be harnessed toward the development of an effective immunotherapeutic strategy. PMID:26697014

  9. TCR down-regulation controls T cell homeostasis

    DEFF Research Database (Denmark)

    Boding, Lasse; Bonefeld, Charlotte Menné; Nielsen, Bodil L

    2009-01-01

    was caused by the combination of reduced thymic output, decreased T cell apoptosis, and increased transition of naive T cells to memory T cells. Experiments with bone marrow chimeric mice confirmed that the CD3gammaLLAA mutation exerted a T cell intrinsic effect on T cell homeostasis that resulted...... in an increased transition of CD3gammaLLAA naive T cells to memory T cells and a survival advantage of CD3gammaLLAA T cells compared with wild-type T cells. The experimental observations were further supported by mathematical modeling of T cell homeostasis. Our study thus identifies an important role of CD3gamma......-mediated TCR down-regulation in T cell homeostasis....

  10. Vitamin D controls T cell antigen receptor signaling and activation of human T cells

    DEFF Research Database (Denmark)

    von Essen, Marina Rode; Kongsbak-Wismann, Martin; Schjerling, Peter

    2010-01-01

    Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering...... led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR...... signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation....

  11. Chimeric Antigen Receptor T Cell (Car T Cell Therapy In Hematology

    Directory of Open Access Journals (Sweden)

    Pinar Ataca

    2015-12-01

    Full Text Available It is well demonstrated that immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation (HSCT. Adoptive T cell transfer has been improved to be more specific and potent and cause less off-target toxicities. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR and chimeric antigen receptor (CAR modified T cells. On July 1, 2014, the United States Food and Drug Administration granted ‘breakthrough therapy’ designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the beneficiaries of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical-clinical studies, effectiveness and drawbacks of this strategy.

  12. Th1-like human T-cell clones recognizing Leishmania gp63 inhibit Leishmania major in human macrophages

    DEFF Research Database (Denmark)

    Kemp, M; Hey, A S; Bendtzen, K

    1994-01-01

    The major surface protease of Leishmania major, gp63, has been suggested as a vaccine candidate for cutaneous leishmaniasis. In this study gp63 was purified from L. major promastigotes. A panel of human T-cell clones recognizing this protein were generated from individuals who had previously had...... self-healing cutaneous leishmaniasis. The T-cell clones expressed CD4, and the alpha chain of the T-cell antigen receptor. GP63 reactive T-cell clones activated by antigen or by immobilized anti-CD3 antibody released relative large amounts of interferon-gamma and no or little interleukin-4, thereby...... resembling Th1 cells. Autologous mononuclear cells and Epstein-Barr virus-transformed B cell lines were equally efficient in presenting the antigen to the T cells. The gp63 reactive T cells induced resistance to infection in cultured human macrophages by L. major. The data confirm that human CD4+ T cells...

  13. Anaplastic Thyroid Cancer with Uncommon Long-term Survival

    Directory of Open Access Journals (Sweden)

    Ai-Hung Liu

    2006-10-01

    Full Text Available In general, most thyroid cancers are indolent and have a slowly progressive course. The exception is anaplastic thyroid cancer. It is one of the most fatal neoplasms in humans, with median survival of 4-12 months. Here, we present a patient with anaplastic thyroid cancer who survived for more than 10 years after diagnosis. A 68-year-old man was incidentally found to have anaplastic thyroid cancer during operation for follicular neoplasm. Total thyroidectomy was performed and hyperfractionated radiotherapy was carried out. After operation, annual follow-up examinations were negative for residual tumor or metastatic lesions. The patient also had chronic obstructive pulmonary disease and unfortunately died of pneumonia in a local hospital 10 years after thyroid operation.

  14. Disabled-2 is a FOXP3 target gene required for regulatory T cell function

    Science.gov (United States)

    Jain, N; Nguyen, H; Friedline, RH; Malhotra, N; Brehm, M; Koyonagi, M; Bix, M; Cooper, JA; Chambers, CA; Kang, J

    2010-01-01

    FOXP3 expressing regulatory T cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. Here we show that in mouse peripheral lymphocytes, the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFβ responses, is exclusively expressed in FOXP3+ regulatory T cells. Dab2 is a direct target of FOXP3 and regulatory T cells lacking DAB2 are functionally impaired in vitro and in vivo. However, not all aspects of Treg cell function are perturbed and DAB2 appears dispensable for Treg cell function in maintaining naïve T cell homeostasis. PMID:19767570

  15. T Cell Phenotype and T Cell Receptor Repertoire in Patients with Major Depressive Disorder

    Directory of Open Access Journals (Sweden)

    Kostas Patas

    2018-02-01

    Full Text Available While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR repertoire in MDD. For this cross-sectional case–control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20, who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20. T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/− cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vβ repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.

  16. Improving the efficacy and safety of engineered T cell therapy for cancer.

    Science.gov (United States)

    Shi, Huan; Liu, Lin; Wang, Zhehai

    2013-01-28

    Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. When aging reaches CD4+ T-cells: phenotypic and functional changes

    Directory of Open Access Journals (Sweden)

    Marco Antonio Moro-García

    2013-05-01

    Full Text Available Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28null T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8+T-cell compartment, these mechanisms ultimately fail with age.

  18. Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells

    Directory of Open Access Journals (Sweden)

    Le Qin

    2017-03-01

    Full Text Available Abstract Background Multiple iterations of chimeric antigen receptors (CARs have been developed, mainly focusing on intracellular signaling modules. However, the effect of non-signaling extracellular modules on the expansion and therapeutic efficacy of CARs remains largely undefined. Methods We generated two versions of CAR vectors, with or without a hinge domain, targeting CD19, mesothelin, PSCA, MUC1, and HER2, respectively. Then, we systematically compared the effect of the hinge domains on the growth kinetics, cytokine production, and cytotoxicity of CAR T cells in vitro and in vivo. Results During in vitro culture period, the percentages and absolute numbers of T cells expressing the CARs containing a hinge domain continuously increased, mainly through the promotion of CD4+ CAR T cell expansion, regardless of the single-chain variable fragment (scFv. In vitro migration assay showed that the hinges enhanced CAR T cells migratory capacity. The T cells expressing anti-CD19 CARs with or without a hinge had similar antitumor capacities in vivo, whereas the T cells expressing anti-mesothelin CARs containing a hinge domain showed enhanced antitumor activities. Conclusions Hence, our results demonstrate that a hinge contributes to CAR T cell expansion and is capable of increasing the antitumor efficacy of some specific CAR T cells. Our results suggest potential novel strategies in CAR vector design.

  19. Cancer Immunotherapy Using CAR-T Cells: From the Research Bench to the Assembly Line.

    Science.gov (United States)

    Gomes-Silva, Diogo; Ramos, Carlos A

    2018-02-01

    The focus of cancer treatment has recently shifted toward targeted therapies, including immunotherapy, which allow better individualization of care and are hoped to increase the probability of success for patients. Specifically, T cells genetically modified to express chimeric antigen receptors (CARs; CAR-T cells) have generated exciting results. Recent clinical successes with this cutting-edge therapy have helped to push CAR-T cells toward approval for wider use. However, several limitations need to be addressed before the widespread use of CAR-T cells as a standard treatment. Here, a succinct background on adoptive T-cell therapy (ATCT)is given. A brief overview of the structure of CARs, how they are introduced into T cells, and how CAR-T cell expansion and selection is achieved in vitro is then presented. Some of the challenges in CAR design are discussed, as well as the difficulties that arise in large-scale CAR-T cell manufacture that will need to be addressed to achieve successful commercialization of this type of cell therapy. Finally, developments already on the horizon are discussed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Autophagy is a critical regulator of memory CD8+ T cell formation

    Science.gov (United States)

    Puleston, Daniel J; Zhang, Hanlin; Powell, Timothy J; Lipina, Elina; Sims, Stuart; Panse, Isabel; Watson, Alexander S; Cerundolo, Vincenzo; Simon, Anna Katharina

    2014-01-01

    During infection, CD8+ T cells initially expand then contract, leaving a small memory pool providing long lasting immunity. While it has been described that CD8+ T cell memory formation becomes defective in old age, the cellular mechanism is largely unknown. Autophagy is a major cellular lysosomal degradation pathway of bulk material, and levels are known to fall with age. In this study, we describe a novel role for autophagy in CD8+ T cell memory formation. Mice lacking the autophagy gene Atg7 in T cells failed to establish CD8+ T cell memory to influenza and MCMV infection. Interestingly, autophagy levels were diminished in CD8+ T cells from aged mice. We could rejuvenate CD8+ T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine. This study reveals a cell intrinsic explanation for poor CD8+ T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity. DOI: http://dx.doi.org/10.7554/eLife.03706.001 PMID:25385531

  1. [Analysis of long-term survivors in anaplastic thyroid carcinoma].

    Science.gov (United States)

    Yoshida, Akira; Matuzu, Kenichi

    2012-07-01

    We analyzed the clinicopathologic and therapeutic factors associated with long-term survival in 449 patients with anaplastic carcinoma registered with the Anaplastic Thyroid Carcinoma Consortium of Japan. Univariate analysis showed a significant relationship between long-term survival of more than 1 year and the following factors: the appearance of acute symptom; WBC thyroid gland after surgery; no distant metastasis at initial diagnosi; complete resection of gross tumor; and administration of external irradiation (40 Gy) and chemotherapy. In multivariate analysis, only tumor diameter (disease.

  2. Pregnancy persistently affects memory T cell populations

    NARCIS (Netherlands)

    Kieffer, Tom E. C.; Faas, Marijke M.; Scherjon, Sicco A.; Prins, Jelmer R.

    Pregnancy is an immune challenge to the maternal immune system. The effects of pregnancy on maternal immunity and particularly on memory T cells during and after pregnancy are not fully known. This observational study aims to show the short term and the long term effects of pregnancy on the

  3. Biomarkers in T cell therapy clinical trials

    Directory of Open Access Journals (Sweden)

    Kalos Michael

    2011-08-01

    Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.

  4. Glutathione Primes T Cell Metabolism for Inflammation

    DEFF Research Database (Denmark)

    Mak, Tak W.; Grusdat, Melanie; Duncan, Gordon S.

    2017-01-01

    the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc...

  5. Altered development of NKT cells, γδ T cells, CD8 T cells and NK cells in a PLZF deficient patient.

    Directory of Open Access Journals (Sweden)

    Maggie Eidson

    Full Text Available In mice, the transcription factor, PLZF, controls the development of effector functions in invariant NKT cells and a subset of NKT cell-like, γδ T cells. Here, we show that in human lymphocytes, in addition to invariant NKT cells, PLZF was also expressed in a large percentage of CD8+ and CD4+ T cells. Furthermore, PLZF was also found to be expressed in all γδ T cells and in all NK cells. Importantly, we show that in a donor lacking functional PLZF, all of these various lymphocyte populations were altered. Therefore, in contrast to mice, PLZF appears to control the development and/or function of a wide variety of human lymphocytes that represent more than 10% of the total PBMCs. Interestingly, the PLZF-expressing CD8+ T cell population was found to be expanded in the peripheral blood of patients with metastatic melanoma but was greatly diminished in patients with autoimmune disease.

  6. MHC class II molecules regulate growth in human T cells

    DEFF Research Database (Denmark)

    Nielsen, M; Odum, Niels; Bendtzen, K

    1994-01-01

    MHC-class-II-positive T cells are found in tissues involved in autoimmune disorders. Stimulation of class II molecules by monoclonal antibodies (mAbs) or bacterial superantigens induces protein tyrosine phosphorylation through activation of protein tyrosine kinases in T cells, and class II signals...... lines tested. Only one of three CD4+, CD45RAhigh, ROhigh T cells responded to class II costimulation. There was no correlation between T cell responsiveness to class II and the cytokine production profile of the T cell in question. Thus, T cell lines producing interferon (IFN)-gamma but not IL-4 (TH1...... modulate several T cell responses. Here, we studied further the role of class II molecules in the regulation of T cell growth. Costimulation of class II molecules by immobilized HLA-DR mAb significantly enhanced interleukin (IL)-2-supported T cell growth of the majority of CD4+, CD45RAlow, ROhigh T cell...

  7. Monitoring circulating gammadelta T cells in cancer patients to optimize gammadelta T cell-based immunotherapy

    OpenAIRE

    Hans-Heinrich eOberg; Christian eKellner; Matthias ePeipp; Susanne eSebens; Sabine eAdam-Klages; Martin eGramatzki; Dieter eKabelitz; Daniela eWesch

    2014-01-01

    The success of gammadelta (gd) T cell-based immunotherapy, where the cytotoxic activity of circulating gd T lymphocytes is activated by nitrogen-containing bisphosphonates (n-BP), or possibly by bispecific antibodies or the combination of both, requires a profound knowledge of patients´ gd T cells. A possible influence of radio- or chemotherapy on gd T cells as well as their reported exhaustion after repetitive treatment with n-BP or their lack of response to various cancers can be easily det...

  8. The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene.

    LENUS (Irish Health Repository)

    Kelleher, Fergal C

    2012-02-01

    The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin\\'s lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system. Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3\\/4 (TMP3\\/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic

  9. T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy

    NARCIS (Netherlands)

    Heijink, D. M.; Kater, A. P.; Hazenberg, M. D.; Hagenbeek, A.; Kersten, M. J.

    2016-01-01

    CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be

  10. T-Cell Immunophenotyping Distinguishes Active From Latent Tuberculosis

    Science.gov (United States)

    Pollock, Katrina M.; Whitworth, Hilary S.; Montamat-Sicotte, Damien J.; Grass, Lisa; Cooke, Graham S.; Kapembwa, Moses S.; Kon, Onn M.; Sampson, Robert D.; Taylor, Graham P.; Lalvani, Ajit

    2013-01-01

    Background. Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection. Methods. A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α). Results. Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPD-specific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone. Conclusions. Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies. PMID:23966657

  11. Anaplastic Thyroid Cancer: A Review of Epidemiology, Pathogenesis, and Treatment

    Directory of Open Access Journals (Sweden)

    Govardhanan Nagaiah

    2011-01-01

    Full Text Available Anaplastic thyroid cancer (ATC is an uncommon malignancy of the thyroid. Only 1-2% of thyroid cancers are anaplastic, but the disease contributes to 14–50% of the mortality with a median survival of 3 to 5 months. Most patients diagnosed with this disease are 65 years of age or older. The incidence of anaplastic thyroid cancer is decreasing worldwide. Most patients present with a rapidly growing neck mass, dysphagia, or voice change. We performed a comprehensive literature search using PubMed focusing on the treatment of anaplastic thyroid cancer including historical review of treatment and outcomes and investigations of new agents and approaches. A total of sixteen chart review and retrospective studies and eleven prospective studies and/or clinical trials were reviewed. The current standard therapeutic approach is to consider the disease as systemic at time of diagnosis and pursue combined modality therapy incorporating cytoreductive surgical resection where feasible and/or chemoradiation either concurrently or sequentially. Doxorubicin is the most commonly used agent, with a response rate of 22%. Several new agents are currently under investigation. Referral of patients for participation in clinical trials is needed.

  12. Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

    International Nuclear Information System (INIS)

    Sabet, Amir; Ahmadzadehfar, Hojjat; Herrlinger, Ulrich; Wilinek, Winfried; Biersack, Hans-Jürgen; Ezziddin, Samer

    2011-01-01

    A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patient's quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition

  13. Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

    Directory of Open Access Journals (Sweden)

    Biersack Hans-Jürgen

    2011-08-01

    Full Text Available Abstract A patient with anaplastic meningioma and lung metastases resistant to conventional treatment underwent radiopeptide therapy with 177Lu- DOTA-octreotate in our institute. The treatment resulted in significant improvement in patient's quality of life and inhibition of tumor progression. This case may eventually help to establish the value of radiopeptide therapy in patients with this rare condition.

  14. Anaplastic ependymoma of the fourth ventricle causing obstrictive ...

    African Journals Online (AJOL)

    The case of fourth ventricular anaplastic epednymoma in a four-year-old child is reported in which the initial presentation was deterioration of the level of consciousness secondary to acute obstructive hydrocephalus. An initial insertion of a ventriculo-peritoneal shunt (V-P) to deal with the acute intracranial hypertension was ...

  15. Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors

    Science.gov (United States)

    Harris, Daniel T.; Kranz, David M.

    2016-01-01

    The tumor-killing properties of T cells provide tremendous opportunities to treat cancer. Adoptive T cell therapies have begun to harness this potential by endowing a functionally diverse repertoire of T cells with genetically modified, tumor-specific recognition receptors. Normally, this antigen recognition function is mediated by an αβ T cell receptor (TCR), but the dominant therapeutic forms currently in development are synthetic constructs called chimeric antigen receptors (CARs). While CAR-based adoptive cell therapies are already showing great promise, their basic mechanistic properties have been studied in less detail compared with those of αβ TCRs. In this review, we compare and contrast various features of TCRs versus CARs, with a goal of highlighting issues that need to be addressed to fully exploit the therapeutic potential of both. PMID:26705086

  16. CD8+ memory T-cell inflation renders compromised CD4+ T-cell-dependent CD8+ T-cell immunity via naïve T-cell anergy

    Directory of Open Access Journals (Sweden)

    Xu A

    2017-06-01

    Full Text Available Aizhang Xu,1,2 Andrew Freywald,3 Yufeng Xie,4 Zejun Li,5 Jim Xiang1,2 1Cancer Research Cluster, Saskatchewan Cancer Agency, 2Department of Oncology, 3Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada; 4Department of Oncology, First Affiliated Hospital, Soochow University, Suzhou, 5Shanghai Veterinary Research Institute, Shanghai, China Abstract: Whether inflation of CD8+ memory T (mT cells, which is often derived from repeated prime-boost vaccinations or chronic viral infections in the elderly, would affect late CD8+ T-cell immunity is a long-standing paradox. We have previously established an animal model with mT-cell inflation by transferring ConA-stimulated monoclonal CD8+ T cells derived from Ova-specific T-cell-receptor transgenic OTI mice into irradiation-induced lymphopenic B6 mice. In this study, we also established another two animal models with mT-cell inflation by transferring, 1 ConA-stimulated monoclonal CD8+ T cells derived from lymphocytic choriomeningitis virus glycoprotein-specific T-cell-receptor transgenic P14 mice, and 2 ConA-stimulated polyclonal CD8+ T cells derived from B6.1 mice into B6 mice with irradiation-induced lymphopenia. We vaccinated these mice with recombinant Ova-expressing Listeria monocytogenes and Ova-pulsed dendritic cells, which stimulated CD4+ T cell-independent and CD4+ T-cell-dependent CD8+ T-cell responses, respectively, and assessed Ova-specific CD8+ T-cell responses by flow cytometry. We found that Ova-specific CD8+ T-cell responses derived from the latter but not the former vaccination were significantly reduced in mice with CD8+ mT-cell inflation compared to wild-type B6 mice. We determined that naïve CD8+ T cells purified from splenocytes of mice with mT-cell inflation had defects in cell proliferation upon stimulation in vitro and in vivo and upregulated T-cell anergy-associated Itch and GRAIL molecules. Taken together, our data reveal that CD8+ mT-cell inflation renders

  17. Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax.

    Science.gov (United States)

    Copeland, K F; Haaksma, A G; Goudsmit, J; Krammer, P H; Heeney, J L

    1994-10-01

    This study set out to determine whether T cell dysfunction associated with HTLV-I led to increased sensitivity of infected cells to apoptosis or, owing to their potential to develop ATL, if infected cells would become resistant to this process. To test this hypothesis we utilized the monoclonal antibody anti-APO-1, which has been demonstrated to induce apoptosis in human T cells. Human T cell lines expressing HTLV-I showed reduced susceptibility to anti-APO-1-induced apoptosis despite expression of high levels of cell surface APO-1. Cell-free supernatant of the Tax-expressing cell line C8166 and heat-inactivated supernatant of the HTLV-I-producing cell line MT2 transferred increased resistance to anti-APO-1 to susceptible Jurkat T cells. Susceptible T cells transfected with an HTLV-I Tax-expressing vector or treated with soluble Tax protein became less susceptible to anti-APO-1-induced cell death. Furthermore, primary human lymphocytes treated with soluble Tax were less susceptible to apoptosis induced by anti-APO-1. The protective effect of Tax in T cell lines and primary human lymphocytes was reversed by the addition of anti-Tax antibodies. Anti-APO-1-induced apoptosis was also found to be inhibited in Jurkat cells by the induction of protein kinase C (PKC) with 12-O-tetradecanoylphorbol-13-acetate (TPA). Resistance to apoptosis conferred by HTLV-I Tax and an active PKC pathway may be factors contributing to the survival of dysregulated HTLV-I-infected T cells prone to the development of adult T cell leukemia.

  18. Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue

    OpenAIRE

    Martinet , Kim ,; Bloquet , Stéphane; Bourgeois , Christine

    2014-01-01

    International audience; BackgroundCD4 T cell lymphopenia is an important T cell defect associated to ageing. Higher susceptibility to infections, cancer, or autoimmune pathologies described in aged individuals is thought to partly rely on T cell lymphopenia. We hypothesize that such diverse effects may reflect anatomical heterogeneity of age related T cell lymphopenia. Indeed, no data are currently available on the impact of ageing on T cell pool recovered from gut associated lymphoid tissue ...

  19. Adoptive T Cell Immunotherapy for Cancer

    Directory of Open Access Journals (Sweden)

    Karlo Perica

    2015-01-01

    Full Text Available Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. In recent years, there has been an increased interest in optimizing this technology in order to make it a clinically feasible treatment. One of the main treatment modalities within cancer immunotherapy has been adoptive T cell therapy (ACT. Using this approach, tumor-specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. In the current review, we revisit some of the major successes of ACT, the major hurdles that have been overcome to optimize ACT, the remaining challenges, and future approaches to make ACT widely available.

  20. Angioimmunoblastic T Cell Lymphoma Mimicking Chronic Urticaria

    Directory of Open Access Journals (Sweden)

    Mohleen Kang

    2016-01-01

    Full Text Available Angioimmunoblastic T cell lymphoma (AITL is a rare but distinct type of T cell lymphoma with an aggressive course and high mortality. Most patients are diagnosed late in the disease and usually present with generalized lymphadenopathy. A minority have skin lesions at the time of diagnosis, more commonly in the form of nonspecific maculopapular rash with or without pruritus. We report a rare case of AITL presenting with chronic, recurrent angioedema and urticaria-like lesions and no palpable peripheral adenopathy. Primary Care physicians, dermatologists, and allergists must maintain a high index of suspicion for cutaneous manifestations of lymphoma, especially if the skin lesions are refractory to standard treatment. Timely diagnosis is essential to improve survival.

  1. T-cell response in human leishmaniasis

    DEFF Research Database (Denmark)

    Kharazmi, A; Kemp, K; Ismail, A

    1999-01-01

    from cutaneous leishmaniasis (CL) responded by IFN-gamma production following stimulation with Leishmania antigens whereas cells from patients recovered from visceral leishmaniasis (VL) showed a mixed pattern of IFN-gamma and IL-4 responses. The cells producing these cytokines were predominantly CD4......In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered......+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans....

  2. The T Cell Response to Staphylococcus aureus

    Science.gov (United States)

    Bröker, Barbara M.; Mrochen, Daniel; Péton, Vincent

    2016-01-01

    Staphylococcus aureus (S. aureus) is a dangerous pathogen and a leading cause of both nosocomial and community acquired bacterial infection worldwide. However, on the other hand, we are all exposed to this bacterium, often within the first hours of life, and usually manage to establish equilibrium and coexist with it. What does the adaptive immune system contribute toward lifelong control of S. aureus? Will it become possible to raise or enhance protective immune memory by vaccination? While in the past the S. aureus-specific antibody response has dominated this discussion, the research community is now coming to appreciate the role that the cellular arm of adaptive immunity, the T cells, plays. There are numerous T cell subsets, each with differing functions, which together have the ability to orchestrate the immune response to S. aureus and hence to tip the balance between protection and pathology. This review summarizes the state of the art in this dynamic field of research. PMID:26999219

  3. T-cell response in human leishmaniasis

    DEFF Research Database (Denmark)

    Kharazmi, A; Kemp, K; Ismail, A

    1999-01-01

    In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered...... from cutaneous leishmaniasis (CL) responded by IFN-gamma production following stimulation with Leishmania antigens whereas cells from patients recovered from visceral leishmaniasis (VL) showed a mixed pattern of IFN-gamma and IL-4 responses. The cells producing these cytokines were predominantly CD4......+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans....

  4. Accumulation of cytolytic CD8{sup +} T cells in B16-melanoma and proliferation of mature T cells in TIS21-knockout mice after T cell receptor stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Min Sook [Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, 164, World cul-ro, Yeongtong-gu, Suwon, Gyeonggi-do 443-380 (Korea, Republic of); Woo, Min-Yeong [Department of Microbiology, Ajou University School of Medicine, 164, World cul-ro, Yeongtong-gu, Suwon, Gyeonggi-do 443-380 (Korea, Republic of); Department of Biomedical Sciences, The Graduate School, Ajou University (Korea, Republic of); Kwon, Daeho [Department of Microbiology, Kwandong University College of Medicine, Gangneung, Gangwon-do 210-701 (Korea, Republic of); Hong, Allen E. [Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, 164, World cul-ro, Yeongtong-gu, Suwon, Gyeonggi-do 443-380 (Korea, Republic of); Song, Kye Yong [Department of Pathology, Chung-Ang University College of Medicine, Dongjak-gu, Seoul 156-756 (Korea, Republic of); Park, Sun [Department of Microbiology, Ajou University School of Medicine, 164, World cul-ro, Yeongtong-gu, Suwon, Gyeonggi-do 443-380 (Korea, Republic of); Lim, In Kyoung [Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, 164, World cul-ro, Yeongtong-gu, Suwon, Gyeonggi-do 443-380 (Korea, Republic of)

    2014-10-01

    In vivo and in vitro effects of TIS21 gene on the mature T cell activation and antitumor activities were explored by employing MO5 melanoma orthograft and splenocytes isolated from the TIS21-knockout (KO) mice. Proliferation and survival of mature T cells were significantly increased in the KO than the wild type (WT) cells, indicating that TIS21 inhibits the rate of mature T cell proliferation and its survival. In MO5 melanoma orthograft model, the KO mice recruited much more CD8{sup +} T cells into the tumors at around day 14 after tumor cell injection along with reduced tumor volumes compared with the WT. The increased frequency of granzyme B{sup +} CD8{sup +} T cells in splenocytes of the KO mice compared with the WT may account for antitumor-immunity of TIS21 gene in the melanoma orthograft. In contrast, reduced frequencies of CD107a{sup +} CD8{sup +} T cells in the splenocytes of KO mice may affect the loss of CD8{sup +} T cell infiltration in the orthograft at around day 19. These results indicate that TIS21 exhibits antiproliferative and proapoptotic effects in mature T cells, and differentially affects the frequencies of granzyme B{sup +} CD8{sup +} T-cells and CD107a{sup +} CD8{sup +} T-cells, thus transiently regulating in vivo anti-tumor immunity. - Highlights: • Constitutive expression of TIS21 in splenocytes and upregulation by TCR stimulation. • Proliferation of mature T-cells in spleen of TIS21KO mice after TCR stimulation. • Inhibition of cell death in mature T-cells of TIS21KO mice compared with the wild type. • Inhibition of melanoma growth in TIS21KO mice and CD8{sup +} T cell infiltration in tumor. • Reduction of CD 107{sup +}CD8{sup +} T cells, but increased granzyme B{sup +} CD8{sup +} T cells in TIS21KO mice.

  5. Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid-Peptide Vaccine.

    Science.gov (United States)

    Anderson, Regan J; Li, Jasmine; Kedzierski, Lukasz; Compton, Benjamin J; Hayman, Colin M; Osmond, Taryn L; Tang, Ching-Wen; Farrand, Kathryn J; Koay, Hui-Fern; Almeida, Catarina Filipa Dos Santos Sa E; Holz, Lauren R; Williams, Geoffrey M; Brimble, Margaret A; Wang, Zhongfang; Koutsakos, Marios; Kedzierska, Katherine; Godfrey, Dale I; Hermans, Ian F; Turner, Stephen J; Painter, Gavin F

    2017-11-17

    The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce T cell responses are of considerable interest because they can target viral proteins that are more likely to be shared between different virus strains and subtypes and hence provide effective cross-reactive IAV immunity. From a practical perspective, such vaccines should induce T cell responses with long-lasting memory, while also being simple to manufacture and cost-effective. Here we describe the synthesis and evaluation of a vaccine platform based on solid phase peptide synthesis and bio-orthogonal conjugation methodologies. The chemical approach involves covalently attaching synthetic long peptides from a virus-associated protein to a powerful adjuvant molecule, α-galactosylceramide (α-GalCer). Strain-promoted azide-alkyne cycloaddition is used as a simple and efficient method for conjugation, and pseudoproline methodology is used to increase the efficiency of the peptide synthesis. α-GalCer is a glycolipid that stimulates NKT cells, a population of lymphoid-resident immune cells that can provide potent stimulatory signals to antigen-presenting cells engaged in driving proliferation and differentiation of peptide-specific T cells. When used in mice, the vaccine induced T cell responses that provided effective prophylactic protection against IAV infection, with the speed of viral clearance greater than that seen from previous viral exposure. These findings are significant because the vaccines are highly defined, quick to synthesize, and easily characterized and are therefore appropriate for large scale affordable manufacture.

  6. T cell differentiation stages identified by molecular and immunologic analysis of the T cell receptor complex in childhood lymphoblastic leukemia.

    Science.gov (United States)

    Mirro, J; Kitchingman, G; Behm, F G; Murphy, S B; Goorha, R M

    1987-03-01

    T cell differentiation was investigated by determining the relationship of T cell receptor (Ti) gene rearrangement and transcription to the expression of surface and cytoplasmic T3 antigen using blast cells from five children with acute lymphoblastic leukemia of thymic origin. Patterns of monoclonal antibody (MoAb) reactivity indicated that these cases were representative of the three recognized stages (I, II, III) of human thymocyte development. The T3 antigen, which becomes linked to the Ti to form a functional T cell receptor complex on mature thymocytes, was expressed on the cell surface in two cases (stage III). However, in the remaining three cases that were surface T3 negative (stages I and II), large amounts of T3 were identified in the cytoplasm by immunoperoxidase staining and flow cytometry. Leukemic blasts from all five patients showed rearranged genes encoding the beta-chain portion of the Ti heterodimer. RNA transcripts of Ti beta-chain genes were also evident in lymphoblasts from all five cases, but transcripts coding for the alpha-chain portion of Ti were found only in cases that expressed T3 on the cell surface. Thus the absence of surface T3 (and presumably Ti) coincides with the absence of Ti alpha-chain RNA, suggesting that transcription of alpha-chain genes is a critical regulatory event in the surface expression of the Ti-T3 complex. Leukemic T cells that rearrange and express Ti beta-chain genes but lack Ti alpha-chain messenger RNA (mRNA) may represent a stage of differentiation analogous to pre-B cells, where heavy-chain immunoglobulin (Ig) genes are rearranged and expressed but light-chain Ig genes are not expressed.

  7. T Cells in Osteoarthritis: Alterations and Beyond

    OpenAIRE

    Li, Yu-sheng; Luo, Wei; Zhu, Shou-an; Lei, Guang-hua

    2017-01-01

    Although osteoarthritis (OA) has been traditionally regarded as a non-inflammatory disease, reports increasingly suggest that it is inflammatory, at least in certain patients. OA patients often exhibit inflammatory infiltration of synovial membranes by macrophages, T cells, mast cells, B cells, plasma cells, natural killer cells, dendritic cells, granulocytes, etc. Although previous reviews have summarized the knowledge of inflammation in the pathogenesis of OA, as far as we know, no report r...

  8. Regulatory T cells: immune suppression and beyond

    OpenAIRE

    Wan, Yisong Y

    2010-01-01

    Foxp3-expressing regulatory T cells (Tregs) were originally identified as critical in maintaining self-tolerance and immune homeostasis. The immunosuppressive functions of Tregs are widely acknowledged and have been extensively studied. Recent studies have revealed many diverse roles of Tregs in shaping the immune system and the inflammatory response. This review will discuss our efforts as well as the efforts of others towards understanding the multifaceted function of Treg...

  9. Improve T Cell Therapy in Neuroblastoma

    Science.gov (United States)

    2014-07-01

    curative treatment is available currently. Hai and colleagues found that the Hedgehog signaling pathway in salivary glands was activated during... salivary gland hypofunction by preserving salivary stem/progenitor cells and the parasympathetic innervation in mice. Similar effects on expression of genes...cytotoxic T lymphocytes without enhancement of regulatory T-cell inhibition. Clin Cancer Res. Clin Cancer Res. 2014 Jan 1;20(1):131-9. Highlited article

  10. Force Dynamics During T Cell Activation

    Science.gov (United States)

    Garcia, David A.; Upadhyaya, Arpita

    T cell activation is an essential step in the adaptive immune response. The binding of the T cell receptor (TCR) with antigen triggers signaling cascades and cell spreading. Physical forces exerted on the TCR by the cytoskeleton have been shown to induce signaling events. While cellular forces are known to depend on the mechanical properties of the cytoskeleton, the biophysical mechanisms underlying force induced activation of TCR-antigen interactions unknown. Here, we use traction force microscopy to measure the force dynamics of activated Jurkat T cells. The movements of beads embedded in an elastic gel serve as a non-invasive reporter of cytoskeletal and molecular motor dynamics. We examined the statistical structure of the force profiles throughout the cell during signaling activation. We found two spatially distinct active regimes of force generation characterized by different time scales. Typically, the interior of the cells was found to be more active than the periphery. Inhibition of myosin motor activity altered the correlation time of the bead displacements indicating additional sources of stochastic force generation. Our results indicate a complex interaction between myosin activity and actin polymerization dynamics in producing cellular forces in immune cells.

  11. Evolution of two prototypic T cell lineages.

    Science.gov (United States)

    Das, Sabyasachi; Li, Jianxu; Hirano, Masayuki; Sutoh, Yoichi; Herrin, Brantley R; Cooper, Max D

    2015-07-01

    Jawless vertebrates, which occupy a unique position in chordate phylogeny, employ leucine-rich repeat (LRR)-based variable lymphocyte receptors (VLR) for antigen recognition. During the assembly of the VLR genes (VLRA, VLRB and VLRC), donor LRR-encoding sequences are copied in a step-wise manner into the incomplete germ-line genes. The assembled VLR genes are differentially expressed by discrete lymphocyte lineages: VLRA- and VLRC-producing cells are T-cell like, whereas VLRB-producing cells are B-cell like. VLRA(+) and VLRC(+) lymphocytes resemble the two principal T-cell lineages of jawed vertebrates that express the αβ or γδ T-cell receptors (TCR). Reminiscent of the interspersed nature of the TCRα/TCRδ locus in jawed vertebrates, the close proximity of the VLRA and VLRC loci facilitates sharing of donor LRR sequences during VLRA and VLRC assembly. Here we discuss the insight these findings provide into vertebrate T- and B-cell evolution, and the alternative types of anticipatory receptors they use for adaptive immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. T Cell Therapy for Nasopharyngeal Carcinoma

    Directory of Open Access Journals (Sweden)

    S Basso, M Zecca, P Merli, A Gurrado, S Secondino, G Quartuccio, I Guido, P Guerini, G Ottonello, N Zavras, R Maccario, P Pedrazzoli, P Comoli

    2011-01-01

    Full Text Available Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.

  13. Clinical trials of CAR-T cells in China

    Directory of Open Access Journals (Sweden)

    Bingshan Liu

    2017-10-01

    Full Text Available Abstract Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications. Multi-target CAR-engineered T cells are also entering clinical trials. T cell receptor-engineered CAR-T and universal CAR-T cells represent new frontiers in CAR-T cell development. In this study, we analyzed the characteristics of CAR constructs and registered clinical trials of CAR-T cells in China and provided a quick glimpse of the landscape of CAR-T studies in China.

  14. Clinical trials of CAR-T cells in China.

    Science.gov (United States)

    Liu, Bingshan; Song, Yongping; Liu, Delong

    2017-10-23

    Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR)-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications. Multi-target CAR-engineered T cells are also entering clinical trials. T cell receptor-engineered CAR-T and universal CAR-T cells represent new frontiers in CAR-T cell development. In this study, we analyzed the characteristics of CAR constructs and registered clinical trials of CAR-T cells in China and provided a quick glimpse of the landscape of CAR-T studies in China.

  15. Cell Density Plays a Critical Role in Ex Vivo Expansion of T Cells for Adoptive Immunotherapy

    Directory of Open Access Journals (Sweden)

    Qiangzhong Ma

    2010-01-01

    Full Text Available The successful ex vivo expansion of a large numbers of T cells is a prerequisite for adoptive immunotherapy. In this study, we found that cell density had important effects on the process of expansion of T cells in vitro. Resting T cells were activated to expand at high cell density but failed to be activated at low cell density. Activated T cells (ATCs expanded rapidly at high cell density but underwent apoptosis at low cell density. Our studies indicated that low-cell-density related ATC death is mediated by oxidative stress. Antioxidants N-acetylcysteine, catalase, and albumin suppressed elevated reactive oxygen species (ROS levels in low-density cultures and protected ATCs from apoptosis. The viability of ATCs at low density was preserved by conditioned medium from high-density cultures of ATCs in which the autocrine survival factor was identified as catalase. We also found that costimulatory signal CD28 increases T cell activation at lower cell density, paralleled by an increase in catalase secretion. Our findings highlight the importance of cell density in T cell activation, proliferation, survival and apoptosis and support the importance of maintaining T cells at high density for their successful expansion in vitro.

  16. Broadening the repertoire of melanoma-associated T-cell epitopes

    DEFF Research Database (Denmark)

    Frøsig, Thomas Mørch; Lyngaa, Rikke Birgitte; Met, Özcan

    2015-01-01

    . Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase...... and TRP-2) that are frequently recognized in patients with the aim of identifying novel T-cell epitopes restricted to HLA-A1, -A3, -A11 and -B7. Using in silico prediction and in vitro confirmation, we identified 127 MHC ligands and analyzed the T-cell responses against these ligands via the MHC multimer...... in the healthy donor group. We confirmed the processing and presentation of HLA-A3-restricted T-cell epitopes from tyrosinase (TQYESGSMDK) and gp100 (LIYRRRLMK) and an HLA-A11-restricted T-cell epitope from gp100 (AVGATKVPR) via the cytolytic T-cell recognition of melanoma cell lines and/or K562 cells expressing...

  17. Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Jennifer P Chou

    Full Text Available Clinical evaluation of immune reconstitution and health status during HIV-1 infection and anti-retroviral therapy (ART is largely based on CD4+ T cell counts and viral load, measures that fail to take into account the CD8+ T cell subset, known to show features of accelerated aging in HIV disease. Here, we compare adenosine deaminase (ADA, glucose uptake receptor 1 (GLUT1, and leucine-rich repeat neuronal 3 (LRRN3 to CD38 expression and telomerase activity, two strong predictors of HIV disease progression. Our analysis revealed that reduced ADA, telomerase activity and LRRN3 gene expression were significantly associated with high CD38 and HLA-DR in CD8+ T cells, with % ADA+ cells being the most robust predictor of CD8+ T cell activation. Our results suggest that ADA, LRRN3 and telomerase activity in CD8+ T cells may serve as novel, clinically relevant biomarkers of immune status in HIV-1 infection, specifically by demonstrating the degree to which CD8+ T cells have progressed to the end stage of replicative senescence. Since chronological aging itself leads to the accumulation of senescent CD8+ T cells, the prolonged survival and resultant increased age of the HIV+ population may synergize with the chronic immune activation to exacerbate both immune decline and age-associated pathologies. The identification and future validation of these new biomarkers may lead to fresh immune-based HIV treatments.

  18. IRF8 dependent classical dendritic cells are essential for intestinal T cell homeostasis

    DEFF Research Database (Denmark)

    Luda, K.; Joeris, Thorsten; Persson, E. K.

    2016-01-01

    The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 dependent DCs have reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8ab+ andCD4+CD8...... dependent DCs in the maintenance of intestinal T cell homeostasis....

  19. Artificial intelligence methods for predicting T-cell epitopes.

    Science.gov (United States)

    Zhao, Yingdong; Sung, Myong-Hee; Simon, Richard

    2007-01-01

    Identifying epitopes that elicit a major histocompatibility complex (MHC)-restricted T-cell response is critical for designing vaccines for infectious diseases and cancers. We have applied two artificial intelligence approaches to build models for predicting T-cell epitopes. We developed a support vector machine to predict T-cell epitopes for an MHC class I-restricted T-cell clone (TCC) using synthesized peptide data. For predicting T-cell epitopes for an MHC class II-restricted TCC, we built a shift model that integrated MHC-binding data and data from T-cell proliferation assay against a combinatorial library of peptide mixtures.

  20. Molecular and cellular insights into T cell exhaustion

    Science.gov (United States)

    Wherry, E. John; Kurachi, Makoto

    2016-01-01

    In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called ‘exhaustion’. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer. PMID:26205583

  1. Nylon wool purification alters the activation of T cells.

    Science.gov (United States)

    Wohler, Jillian E; Barnum, Scott R

    2009-02-01

    Purification of lymphocytes, particularly T cells, is commonly performed using nylon wool. This enrichment method selectively retains B cells and some myeloid cells allowing a significantly more pure T cell population to flow through a nylon wool column. T cells purified in this fashion are assumed to be unaltered and functionally naïve, however some studies have suggested aberrant in vitro T cell responses after nylon wool treatment. We found that nylon wool purification significantly altered T cell proliferation, expression of activation markers and production of cytokines. Our results suggest that nylon wool treatment modifies T cell activation responses and that caution should be used when choosing this purification method.

  2. A comparative evaluation of supervised and unsupervised representation learning approaches for anaplastic medulloblastoma differentiation

    Science.gov (United States)

    Cruz-Roa, Angel; Arevalo, John; Basavanhally, Ajay; Madabhushi, Anant; González, Fabio

    2015-01-01

    Learning data representations directly from the data itself is an approach that has shown great success in different pattern recognition problems, outperforming state-of-the-art feature extraction schemes for different tasks in computer vision, speech recognition and natural language processing. Representation learning applies unsupervised and supervised machine learning methods to large amounts of data to find building-blocks that better represent the information in it. Digitized histopathology images represents a very good testbed for representation learning since it involves large amounts of high complex, visual data. This paper presents a comparative evaluation of different supervised and unsupervised representation learning architectures to specifically address open questions on what type of learning architectures (deep or shallow), type of learning (unsupervised or supervised) is optimal. In this paper we limit ourselves to addressing these questions in the context of distinguishing between anaplastic and non-anaplastic medulloblastomas from routine haematoxylin and eosin stained images. The unsupervised approaches evaluated were sparse autoencoders and topographic reconstruct independent component analysis, and the supervised approach was convolutional neural networks. Experimental results show that shallow architectures with more neurons are better than deeper architectures without taking into account local space invariances and that topographic constraints provide useful invariant features in scale and rotations for efficient tumor differentiation.

  3. Infection of CD4+ T lymphocytes by the human T cell leukemia virus type 1 is mediated by the glucose transporter GLUT-1: Evidence using antibodies specific to the receptor's large extracellular domain

    International Nuclear Information System (INIS)

    Jin, Qingwen; Agrawal, Lokesh; VanHorn-Ali, Zainab; Alkhatib, Ghalib

    2006-01-01

    To analyze HTLV-1 cytotropism, we developed a highly sensitive vaccinia virus-based assay measuring activation of a reporter gene upon fusion of two distinct cell populations. We used this system in a functional cDNA screening to isolate and confirm that the glucose transporter protein 1 (GLUT-1) is a receptor for HTLV-1. GLUT-1 is a ubiquitously expressed plasma membrane glycoprotein with 12 transmembrane domains and 6 extracellular loops (ECL). We demonstrate for the first time that peptide antibodies (GLUT-IgY) raised in chicken to the large extracellular loop (ECL1) detect GLUT-1 at the cell surface and inhibit envelope (Env)-mediated fusion and infection. Efficient GLUT-IgY staining was detected with peripheral blood CD4 + lymphocytes purified by positive selection. Further, GLUT-IgY caused efficient inhibition of Env-mediated fusion and infection of CD4 + T and significantly lower inhibition of CD8 + T lymphocytes. The specificity of GLUT-IgY antibodies to GLUT-1 was demonstrated by ECL1 peptide competition studies. Grafting ECL1 of GLUT-1 onto the receptor-negative GLUT-3 conferred significant receptor activity. In contrast, grafting ECL1 of GLUT-3 onto GLUT-1 resulted in a significant loss of the receptor activity. The ECL1-mediated receptor activity was efficiently blocked with four different human monoclonal antibody (HMab) to HTLV-1 Env. The ECL1-derived peptide blocked HTLV-1 Env-mediated fusion with several nonhuman mammalian cell lines. The results demonstrate the utilization of cell surface GLUT-1 in HTLV-1 infection of CD4 + T lymphocytes and implicate a critical role for the ECL1 region in viral tropism

  4. Protothecosis in a patient with T cell lymphocytic leukemia.

    Science.gov (United States)

    Fernández, Mariana S; Rojas, Florencia D; Cattana, María E; Mussin, Javier E; de Los Ángeles Sosa, María; Benzoni, Carlos D; Giusiano, Gustavo E

    Human protothecosis is a rare infection caused by algae of the genus Prototheca. Prototheca wickerhamii has been recognized as the main species that causes infection in immunocompromised hosts with deficits in innate or cellular immunity. We report a case of persisting subcutaneous protothecosis in a patient with T-cell large granular lymphocyte leukemia, who also presented a history of disseminated histoplasmosis. Copyright © 2017 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells.

    Science.gov (United States)

    Stauss, Hans J; Thomas, Sharyn; Cesco-Gaspere, Michela; Hart, Daniel P; Xue, Shao-An; Holler, Angelika; King, Judy; Wright, Graham; Perro, Mario; Pospori, Constantina; Morris, Emma

    2008-01-01

    Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies.

  6. Next-generation detection of antigen-responsive T cells using DNA barcode-labeled peptidemajor histocompatibility complex I multimers

    DEFF Research Database (Denmark)

    Bentzen, Amalie Kai; Marquard, Andrea Marion; Lyngaa, Rikke Birgitte

    2016-01-01

    diversity of T cell recognition in humans. Consequently it has been impossible to comprehensively analyze T cell responsiveness in cancer, infectious and autoimmune diseases. We present and validate a novel technology that enables parallel detection of numerous different peptide-MHC responsive T cells...... in asingle sample using >1000 different peptide-MHC multimers labeled with individual DNA barcodes. After isolation of MHC multimer binding T cells their recognition are revealed by amplification and sequencing of the MHC multimer-associated DNA barcodes. The relative frequency of the sequenced DNA barcodes...... originating from a given peptide-MHC motif relates to the size of the antigenresponsive T cell population. We have demonstrated the use of large panels of >1000 DNA barcoded MHC multimers for detection of rare T cell populations of virus and cancer-restricted origin in various tissues and compared...

  7. The neonatal CD8+ T cell repertoire rapidly diversifies during persistent viral infection1

    Science.gov (United States)

    Venturi, Vanessa; Nzingha, Kito; Amos, Timothy G.; Charles, Wisler C.; Dekhtiarenko, Iryna; Cicin-Sain, Luka; Davenport, Miles P.; Rudd, Brian D.

    2015-01-01

    Cytomegalovirus (CMV) is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment and sensorineural hearing loss. Previous reports have shown that CD8+ T cells are required to control viral replication and significant numbers of CMV-specific CD8+ T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8+ T cells in the brain during latency remains largely undefined. In this report, we used T cell receptor (TCR) sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue resident memory CD8+ T cells, we hypothesized that neonatal TCR clonotypes would be ‘locked-in’ the brain and persist into adulthood. Surprisingly, we found that the antigen-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8+ T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain antigen-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8+ T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life. PMID:26764033

  8. A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression.

    Science.gov (United States)

    Christopoulos, Petros; Dopfer, Elaine P; Malkovsky, Miroslav; Esser, Philipp R; Schaefer, Hans-Eckart; Marx, Alexander; Kock, Sylvia; Rupp, Nicole; Lorenz, Myriam R; Schwarz, Klaus; Harder, Jan; Martin, Stefan F; Werner, Martin; Bogdan, Christian; Schamel, Wolfgang W A; Fisch, Paul

    2015-04-01

    The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αβ T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his "untouched" naive CD4(+) T cells. Biochemical analysis revealed that his γδ and αβ T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good's syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αβ T cells and an increased susceptibility to infections. Copyright © 2015 by The American Association of Immunologists, Inc.

  9. Evaluation of clinical trial eligibility and prognostic indices in a population-based cohort of systemic peripheral T-cell lymphomas from the Danish Lymphoma Registry

    DEFF Research Database (Denmark)

    Pedersen, Martin Bjerregård; Hamilton-Dutoit, Stephen Jacques; Bendix, Knud

    2014-01-01

    Clinical trials (CTs) are needed to improve the outcome for peripheral T-cell lymphomas (PTCL), and accrual into CTs is one of the main recommendations in international treatment guidelines. The use of risk-adapted strategies has been suggested as a way to optimize treatment outcome in PTCL......-ALAT and measurable tumour lesion), patients were subdivided into four groups: 'younger fit', 'elderly fit', 'frail' and 'not CT eligible'. International prognostic index (IPI), prognostic index for T-cell lymphoma (PIT) and anaplastic lymphoma kinase (ALK) protein expression were tested at subtype-specific level....... Overall, 41% of the patients were considered eligible for interventional CTs implicating curatively intended multiagent chemotherapy, including, if considered appropriate, consolidating stem cell transplantation (SCT), as part of the upfront management strategy. Moreover, 28% was elderly fit and eligible...

  10. Natural Killer T Cells in Cancer Immunotherapy

    Science.gov (United States)

    Nair, Shiny; Dhodapkar, Madhav V.

    2017-01-01

    Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells. Finally, we discuss future perspectives to better harness the potential of NKT cells for cancer therapy. PMID:29018445

  11. Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction

    Science.gov (United States)

    Schietinger, Andrea; Greenberg, Philip D.

    2013-01-01

    CD8 T cell activation and differentiation is tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional `states' have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with emphasis on (i) T cell tolerance to self-antigens (self-tolerance), (ii) T cell exhaustion during chronic infections, and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal. PMID:24210163

  12. Cutting edge: Dab2 is a FOXP3 target gene required for regulatory T cell function.

    Science.gov (United States)

    Jain, Nitya; Nguyen, Hai; Friedline, Randall H; Malhotra, Nidhi; Brehm, Michael; Koyanagi, Madoka; Bix, Mark; Cooper, Jonathan A; Chambers, Cynthia A; Kang, Joonsoo

    2009-10-01

    FOXP3-expressing regulatory T (Treg) cells are vital for maintaining peripheral T cell tolerance and homeostasis. The mechanisms by which FOXP3 target genes orchestrate context-dependent Treg cell function are largely unknown. In this study we show that in mouse peripheral lymphocytes the Drosophila Disabled-2 (Dab2) homolog, a gene that is involved in enhancing TGFbeta responses, is exclusively expressed in FOXP3+ regulatory T cells. Dab2 is a direct target of FOXP3, and regulatory T cells lacking DAB2 are functionally impaired in vitro and in vivo. However, not all aspects of Treg cell function are perturbed, and DAB2 appears to be dispensable for Treg cell function in maintaining naive T cell homeostasis.

  13. Metabolism, migration and memory in cytotoxic T cells

    OpenAIRE

    FINLAY, DAVID

    2011-01-01

    PUBLISHED The transcriptional and metabolic programmes that control CD8(+) T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8(+) T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metab...

  14. Anaplastic carcinoma of thyroid gland with widespread soft tissue metastasis: an unusual presentation.

    Science.gov (United States)

    Hassan, Muhammad; Janjua, Taimoor Khalid; Afridi, Hira Khan; Zahid, Naila Anjum

    2017-07-13

    Anaplastic thyroid cancer is the rarest tumour of the thyroid gland, representing only 2% of clinically recognised thyroid cancers. The most common metastatic sites are lungs, followed by the intrathoracic and neck lymph nodes. We report the case of a 62-year-old woman who presented to our setting with multiple soft tissue nodules, thyroid mass, head swelling and weight loss. Radiological investigation showed a large thyroid mass with widespread metastasis in subcutaneous tissues of both upper limbs, chest and abdomen. Metastasis was also found in lungs, skull and adrenal glands after which the patient was diagnosed with stage IVc anaplastic thyroid carcinoma (ATC). After careful consideration of patient's clinical condition with multiple poor prognostic factors, medical therapy was withheld and she was discharged on hospice care. The patient expired after 1 month. In ATC, metastasis to subcutaneous tissue is an extremely rare occurrence of which there is hardly any evidence in literature. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. Development of alphabeta T cells in the human thymus

    NARCIS (Netherlands)

    Spits, Hergen

    2002-01-01

    The thymus is the main producer of alphabeta T cells and is, therefore, crucial for a normal immune system. The intrathymic developmental pathway of human alphabeta T cells has now been delineated. The production of new T cells by the thymus decreases with age, and the thymus was thought to be

  16. The TLX1 oncogene drives aneuploidy in T cell transformation

    NARCIS (Netherlands)

    K. de Keersmaecker (Kim); P.J. Real (Pedro); G.D. Gatta; T. Palomero (Teresa); M.L. Sulis; V. Tosello (Valeria); P. van Vlierberghe (Pieter); K. Barnes (Kelly); M. Castillo (Mireia); X. Sole (Xavier); M. Hadler (Michael); J. Lenz (Jack); P.D. Aplan (Peter); M. Kelliher (Michelle); B.L. Kee (Barbara); P.P. Pandolfi; D. Kappes (Dietmar); F. Gounari (Fotini); H. Petrie (Howard); J. van der Meulen (Joni); F. Speleman (Franki); E. Paietta (Elisabeth); J. Racevskis (Janis); P.H. Wiernik (Peter); J. Rowe (Jacob); J. Soulier (Jean); D. Avran (David); H. Cavé (Hélène); N. Dastugue (Nicole); S. Raimondi (Susana); J.P.P. Meijerink (Jules); C. Cordon-Cardo (Carlos); A. Califano (Andrea); A.A. Ferrando (Adolfo)

    2010-01-01

    textabstractThe TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show

  17. A response calculus for immobilized T cell receptor ligands

    DEFF Research Database (Denmark)

    Andersen, P S; Menné, C; Mariuzza, R A

    2001-01-01

    To address the molecular mechanism of T cell receptor (TCR) signaling, we have formulated a model for T cell activation, termed the 2D-affinity model, in which the density of TCR on the T cell surface, the density of ligand on the presenting surface, and their corresponding two-dimensional affini...

  18. T-cell dynamics in chronic viral infection

    NARCIS (Netherlands)

    Veel, E.M.

    2014-01-01

    In this thesis we investigate how chronic HIV and CMV infections impact on the human T-cell compartment. How untreated HIV infection affects the turnover of human CD4+ and CD8+ T cells is described in chapter 2. In this chapter, T-cell turnover in untreated HIV infected individuals is compared to

  19. Evolution of MHC-based technologies used for detection of antigen-responsive T cells.

    Science.gov (United States)

    Bentzen, Amalie Kai; Hadrup, Sine Reker

    2017-05-01

    T cell-mediated recognition of peptide-major histocompatibility complex (pMHC) class I and II molecules is crucial for the control of intracellular pathogens and cancer, as well as for stimulation and maintenance of efficient cytotoxic responses. Such interactions may also play a role in the development of autoimmune diseases. Novel insights into this mechanism are crucial to understanding disease development and establishing new treatment strategies. MHC multimers have been used for detection of antigen-responsive T cells since the first report by Altman et al. showed that tetramerization of pMHC class I molecules provided sufficient stability to T cell receptor (TCR)-pMHC interactions, allowing detection of MHC multimer-binding T cells using flow cytometry. Since this breakthrough the scientific community has aimed for expanding the capacity of MHC multimer-based detection technologies to facilitate large-scale epitope discovery and immune monitoring in limited biological material. Screening of T cell specificity using large libraries of pMHC molecules is suitable for analyses of T cell recognition potentially at genome-wide levels rather than analyses restricted to a selection of model antigens. Such strategies provide novel insights into the immune specificities involved in disease development and response to immunotherapy, and extend fundamental knowledge related to T cell recognition patterns and cross-recognition by TCRs. MHC multimer-based technologies have now evolved from detection of 1-2 different T cell specificities per cell sample, to include more than 1000 evaluable pMHC molecules using novel technologies. Here, we provide an overview of MHC multimer-based detection technologies developed over two decades, focusing primarily on MHC class I interactions.

  20. Unraveling Natural Killer T-Cells Development

    Directory of Open Access Journals (Sweden)

    Sabrina Bianca Bennstein

    2018-01-01

    Full Text Available Natural killer T-cells are a subset of innate-like T-cells with the ability to bridge innate and adaptive immunity. There is great interest in harnessing these cells to improve tumor therapy; however, greater understanding of invariant NKT (iNKT cell biology is needed. The first step is to learn more about NKT development within the thymus. Recent studies suggest lineage separation of murine iNKT cells into iNKT1, iNKT2, and iNKT17 cells instead of shared developmental stages. This review will focus on these new studies and will discuss the evidence for lineage separation in contrast to shared developmental stages. The author will also highlight the classifications of murine iNKT cells according to identified transcription factors and cytokine production, and will discuss transcriptional and posttranscriptional regulations, and the role of mammalian target of rapamycin. Finally, the importance of these findings for human cancer therapy will be briefly discussed.

  1. Use of tracheal stenting in the palliation of anaplastic thyroid carcinoma: tertiary centre experience.

    Science.gov (United States)

    Varadharajan, K; Mathew, R; Odutoye, B; Williamson, P; Madden, B

    2015-06-01

    Anaplastic thyroid carcinoma is rare but carries a poor prognosis. Anaplastic thyroid carcinoma leads to tracheal compression, airway compromise and eventually death. Airway compromise, a particularly distressing symptom, can be palliated with tracheal stenting. A retrospective case note analysis was conducted of patients diagnosed with anaplastic thyroid carcinoma between July 2003 and July 2013. Twelve patients with anaplastic thyroid carcinoma were identified. Four patients underwent palliative tracheal stenting. Three patients had no dyspnoea at the time of stenting. Two stented patients subsequently developed dyspnoea secondary to stent migration; this was managed successfully with stent exchange. The other stented patient remained asymptomatic with regards to dyspnoea. All non-stented patients died with or from airway compromise. Tracheal stenting is a relatively safe and effective method for palliation of distressing airway symptoms in patients with anaplastic thyroid carcinoma. Early prophylactic tracheal stenting in anaplastic thyroid carcinoma may be an effective option to prevent development of airway compromise as the disease progresses.

  2. Elevated and cross‐responsive CD1a‐reactive T cells in bee and wasp venom allergic individuals

    Science.gov (United States)

    Subramaniam, Sumithra; Aslam, Aamir; Misbah, Siraj A.; Salio, Mariolina; Cerundolo, Vincenzo; Moody, D Branch

    2015-01-01

    The role of CD1a‐reactive T cells in human allergic disease is unknown. We have previously shown that circulating CD1a‐reactive T cells recognize neolipid antigens generated by bee and wasp venom phospholipase, and here tested the hypothesis that venom‐responsive CD1a‐reactive T cells associate with venom allergy. Circulating T cells from bee and wasp venom allergic individuals, before and during immunotherapy, were exposed to CD1a‐transfected K562 cells in the presence of wasp or bee venom. T‐cell response was evaluated based on IFNγ, GM‐CSF, and IL‐13 cytokine production. Venom allergic individuals showed significantly higher frequencies of IFN‐γ, GM‐CSF, and IL‐13 producing CD1a‐reactive T cells responsive to venom and venom‐derived phospholipase than healthy individuals. Venom‐responsive CD1a‐reactive T cells were cross‐responsive between wasp and bee suggesting shared pathways of allergenicity. Frequencies of CD1a‐reactive T cells were initially induced during subcutaneous immunotherapy, peaking by weeks 5, but then reduced despite escalation of antigen dose. Our current understanding of venom allergy and immunotherapy is largely based on peptide and protein‐specific T cell and antibody responses. Here, we show that lipid antigens and CD1a‐reactive T cells associate with the allergic response. These data have implications for mechanisms of allergy and approaches to immunotherapy. PMID:26518614

  3. Killing of targets by CD8 T cells in the mouse spleen follows the law of mass action.

    Directory of Open Access Journals (Sweden)

    Vitaly V Ganusov

    2011-01-01

    Full Text Available It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response.

  4. Killing of targets by CD8 T cells in the mouse spleen follows the law of mass action.

    Science.gov (United States)

    Ganusov, Vitaly V; Barber, Daniel L; De Boer, Rob J

    2011-01-24

    It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response.

  5. Malignant T cells exhibit CD45 resistant Stat 3 activation and proliferation in cutaneous T cell lymphoma

    DEFF Research Database (Denmark)

    Krejsgaard, T; Helvad, Rikke; Ralfkiær, Elisabeth

    2010-01-01

    -cell lymphoma (CTCL), the malignant T cells exhibit constitutive activation of the Jak3/Stat3 signalling pathway and uncontrolled proliferation. We show that CD45 expression is down-regulated on malignant T cells when compared to non-malignant T cells established from CTCL skin lesions. Moreover, CD45 cross...

  6. ZFAT plays critical roles in peripheral T cell homeostasis and its T cell receptor-mediated response

    International Nuclear Information System (INIS)

    Doi, Keiko; Fujimoto, Takahiro; Okamura, Tadashi; Ogawa, Masahiro; Tanaka, Yoko; Mototani, Yasumasa; Goto, Motohito; Ota, Takeharu; Matsuzaki, Hiroshi; Kuroki, Masahide; Tsunoda, Toshiyuki; Sasazuki, Takehiko; Shirasawa, Senji

    2012-01-01

    Highlights: ► We generated Cd4-Cre-mediated T cell-specific Zfat-deficient mice. ► Zfat-deficiency leads to reduction in the number of the peripheral T cells. ► Impaired T cell receptor-mediated response in Zfat-deficient peripheral T cells. ► Decreased expression of IL-7Rα, IL-2Rα and IL-2 in Zfat-deficient peripheral T cells. ► Zfat plays critical roles in peripheral T cell homeostasis. -- Abstract: ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in apoptosis, development and primitive hematopoiesis. Zfat is highly expressed in T- and B-cells in the lymphoid tissues, however, its physiological function in the immune system remains totally unknown. Here, we generated the T cell-specific Zfat-deficient mice and demonstrated that Zfat-deficiency leads to a remarkable reduction in the number of the peripheral T cells. Intriguingly, a reduced expression of IL-7Rα and the impaired responsiveness to IL-7 for the survival were observed in the Zfat-deficient T cells. Furthermore, a severe defect in proliferation and increased apoptosis in the Zfat-deficient T cells following T cell receptor (TCR) stimulation was observed with a reduced IL-2Rα expression as well as a reduced IL-2 production. Thus, our findings reveal that Zfat is a critical regulator in peripheral T cell homeostasis and its TCR-mediated response.

  7. The Role of Lymphatic Niches in T Cell Differentiation

    Science.gov (United States)

    Capece, Tara; Kim, Minsoo

    2016-01-01

    Long-term immunity to many viral and bacterial pathogens requires CD8+ memory T cell development, and the induction of long-lasting CD8+ memory T cells from a naïve, undifferentiated state is a major goal of vaccine design. Formation of the memory CD8+ T cell compartment is highly dependent on the early activation cues received by naïve CD8+ T cells during primary infection. This review aims to highlight the cellularity of various niches within the lymph node and emphasize recent evidence suggesting that distinct types of T cell activation and differentiation occur within different immune contexts in lymphoid organs. PMID:27306645

  8. Regulation of Mu Opioid Receptor Expression in Developing T Cells

    OpenAIRE

    Zhang, Lily; Belkowski, Judith Sliker; Briscoe, Tammi; Rogers, Thomas J.

    2012-01-01

    We have previously reported that functionally active μ-opioid receptors (MOR) are constitutively expressed at relatively low levels by developing T cells in the thymus. However, very little is known about the regulation of MOR expression by immature T cells. In this report, we first attempted to determine the effect of T cell receptor-induced T cell activation on the expression of MOR. We activated T cells with either the combination of anti-CD3 and CD28, or with superantigen, and observed a ...

  9. Potential roles of self-reactive T cells in autoimmunity

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2014-01-01

    that recognize proteins involved in three, well-defined immunosuppressive mechanisms: (1) inhibitory T cell pathways (i.e., PD-L1), (2) regulatory T cells (i.e., Foxp3(+)), and (3) metabolic enzymes, like indoleamine-2,3-dioxygenase. Cytotoxic T cells can eliminate regulatory cells, thereby suppressing and....../or delaying local immune suppression; conversely, regulatory CD4(+) and non-cytotoxic CD8(+) T cells enhance target-mediated immune suppression. The apparent lack of tolerance against endogenous proteins expressed by regulatory cells is intriguing, because it suggests that self-reactive T cells play a general...

  10. Chimeric antigen receptor T-cell therapy for solid tumors

    Directory of Open Access Journals (Sweden)

    Kheng Newick

    2016-01-01

    Full Text Available Chimeric antigen receptor (CAR T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies (e.g., CD19 CARs in leukemias. This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment.

  11. Neoantigen landscape dynamics during human melanoma-T cell interactions

    DEFF Research Database (Denmark)

    Verdegaal, Els M. E.; De Miranda, Noel F. C. C.; Visser, Marten

    2016-01-01

    is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either...... by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer...

  12. CD8+ T cells in inflammatory demyelinating disease

    DEFF Research Database (Denmark)

    Weiss, Hanne A; Millward, Jason M; Owens, Trevor

    2007-01-01

    We review the contribution made by CD8+ T cells to inflammation in the central nervous system (CNS) in Multiple Sclerosis (MS), and discuss their role in the animal model Experimental Autoimmune Encephalomyelitis (EAE). We show that the inflammatory cytokines interferon-gamma and interleukin-17...... are differentially regulated in CNS-infiltrating CD4+ and CD8+ T cells in EAE, and that CD8+ T cells regulate disease. In MS, CD8+ T cells appear to play a role in promotion of disease, so cytokine regulation is likely different in CD8+ T cells in MS and EAE...

  13. Adoptive T cell therapy: Addressing challenges in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Yee Cassian

    2005-04-01

    Full Text Available Abstract Adoptive T cell therapy involves the ex vivo selection and expansion of effector cells for the treatment of patients with cancer. In this review, the advantages and limitations of using antigen-specific T cells are discussed in counterpoint to vaccine strategies. Although vaccination strategies represent more readily available reagents, adoptive T cell therapy provides highly selected T cells of defined phenotype, specificity and function that may influence their biological behavior in vivo. Adoptive T cell therapy offers not only translational opportunities but also a means to address fundamental issues in the evolving field of cancer immunotherapy.

  14. Primary intestinal T cell lymphomas in Indian patients - In search of enteropathic T cell lymphoma

    Directory of Open Access Journals (Sweden)

    Shet Tanuja

    2010-07-01

    Full Text Available Objective: This series of six intestinal T cell lymphomas (ITCL attempts to document enteropathy-associated T cell lymphoma (EATCL in India. Materials and Methods: A total of six ITCL were selected from 170 gastrointestinal lymphomas in last 10 years. Results: The cases studied included EATCL (4, ITCL with a CD4 positive phenotype (1 and ITCL NK/T cell type (1. Of the four EATCL, two occurred in the ileum, one in right colon and one in duodenum. In three EATCL cases, there was history of celiac disease or lactose intolerance and enteropathic changes were noted in the adjacent mucosa. These tumors had CD3+/CD8+/CD56 (+/-/CD4-/ Granzyme B+ immunophenotype. One EATCL was monomorphic small cell type (type II EATCL with a CD3+/CD8-CD56+/CD4-/ Granzyme B+ phenotype. EBER- ISH (Epstein Barr virus coded RNA′s- in situ hybridization revealed positive tumor cells in ITCL NK/T cell type and in bystander cells in three EATCL. Conclusion: ITCL are rare in Indian patients but do occur and comprise a mixture of the enteropathic and non-enteropathic subtypes.

  15. MMP19 is essential for T cell development and T cell-mediated cutaneous immune responses

    Czech Academy of Sciences Publication Activity Database

    Beck, Inken; Ruckert, R.; Brandt, K.; Mueller, M.S.; Sadowski, T.; Brauer, R.; Schirmacher, P.; Mentlein, R.; Sedláček, Radislav

    2008-01-01

    Roč. 3, č. 6 (2008), e2343-e2343 E-ISSN 1932-6203 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : matrix metalloproteinase * T cell * immune response Subject RIV: EB - Genetics ; Molecular Biology

  16. Optimal T cell cross-reactivity and the role of regulatory T cells

    NARCIS (Netherlands)

    Saeki, Koichi; Doekes, Hilje M.; De Boer, Rob J.

    2015-01-01

    The T lymphocytes of the adaptive immune system constitute a highly diverse repertoire of clones expressing a unique T cell receptor (TCR). It has been argued that TCRs are cross-reactive, meaning that one receptor can recognize a multitude of epitopes. Cross-reactivity between self and foreign

  17. Optimal T cell cross-reactivity and the role of regulatory T cells

    NARCIS (Netherlands)

    Saeki, Koichi; Doekes, Hilje M; De Boer, Rob J; Sub Theoretical Biology; Sub Theoretical Biology & Bioinformatics; Theoretical Biology and Bioinformatics

    2014-01-01

    The T lymphocytes of the adaptive immune system constitute a highly diverse repertoire of clones expressing a unique T cell receptor (TCR). It has been argued that TCRs are cross-reactive, meaning that one receptor can recognize a multitude of epitopes. Cross-reactivity between self and foreign

  18. T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock

    NARCIS (Netherlands)

    Hazenberg, M. D.; Hamann, D.; Schuitemaker, H.; Miedema, F.

    2000-01-01

    HIV-1 infection is characterized by a gradual loss of CD4+ T cells and progressive immune deficiency that leads to opportunistic infections, otherwise rare malignancies and ultimately death. Extensive research over the past two decades has increased our insight into the pathogenic mechanisms

  19. Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis

    Science.gov (United States)

    Autoimmune diseases are common, disabling immune disorders affecting millions of people. Recent studies indicate that dysregulated balance of different CD4+ T-cell subpopulations plays a key role in immune pathogenesis of several major autoimmune diseases. Green tea and its active ingredient, epigal...

  20. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases

    Science.gov (United States)

    One of the proposed health benefits of consuming green tea is its protective effect on autoimmune diseases. Research on the immunopathogenesis of autoimmune diseases has made significant progression in the past few years and several key concepts have been revised. T cells, particularly CD4+ T helper...

  1. Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis.

    Science.gov (United States)

    Ladel, C H; Blum, C; Dreher, A; Reifenberg, K; Kaufmann, S H

    1995-10-01

    Tuberculosis is a chronic infectious disease which causes major health problems globally. Although acquired resistance crucially depends on alpha/beta lymphocytes, circumstantial evidence suggests that, in addition, gamma/delta T lymphocytes contribute to protection against tuberculosis. We have studied Mycobacterium tuberculosis infection in TcR-delta-/- or TcR-beta-/- gene deletion mutants which completely lack gamma/delta T cells or alpha/beta T cells, respectively. Low inocula of M. tuberculosis led to death of TcR-beta-/- mice and transient disease exacerbation in TcR-delta-/- mutants. Infection with higher inocula caused rapid death of TcR-delta-/- mice. The development of and bacterial containment in granulomatous lesions was markedly impaired in TcR-beta-/-, and less severely affected in TcR-delta-/- mutants. Mycobacteria-induced IFN-gamma production by spleen cells in vitro was almost abolished in TcR-beta-/- and virtually unaffected in TcR-delta-/- mice. Our data confirm the crucial role of alpha/beta T cells in protection against established tuberculosis and formally prove a protective role of gamma/delta T cells in early tuberculosis.

  2. Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax

    NARCIS (Netherlands)

    Copeland, K. F.; Haaksma, A. G.; Goudsmit, J.; Krammer, P. H.; Heeney, J. L.

    1994-01-01

    This study set out to determine whether T cell dysfunction associated with HTLV-I led to increased sensitivity of infected cells to apoptosis or, owing to their potential to develop ATL, if infected cells would become resistant to this process. To test this hypothesis we utilized the monoclonal

  3. Role of the T cell receptor ligand affinity in T cell activation by bacterial superantigens

    DEFF Research Database (Denmark)

    Andersen, P S; Geisler, C; Buus, S

    2001-01-01

    Similar to native peptide/MHC ligands, bacterial superantigens have been found to bind with low affinity to the T cell receptor (TCR). It has been hypothesized that low ligand affinity is required to allow optimal TCR signaling. To test this, we generated variants of Staphylococcus enterotoxin C3...

  4. Role of T cell receptor affinity in the efficacy and specificity of adoptive T cell therapies

    Directory of Open Access Journals (Sweden)

    Jennifer D. Stone

    2013-08-01

    Full Text Available Over the last several years, there has been considerable progress in the treatment of cancer using gene modified adoptive T cell therapies. Two approaches have been used, one involving the introduction of a conventional alpha-beta T cell receptor (TCR against a pepMHC cancer antigen, and the second involving introduction of a chimeric antigen receptor (CAR consisting of a single-chain antibody as an Fv fragment (scFv linked to transmembrane and signaling domains. In this review, we focus on one aspect of TCR-mediated adoptive T cell therapies, the impact of the affinity of the alpha-beta TCR for the pepMHC cancer antigen on both efficacy and specificity. We discuss the advantages of higher affinity TCRs in mediating potent activity of CD4 T cells. This is balanced with the potential disadvantage of higher affinity TCRs in mediating greater self-reactivity against a wider range of structurally similar antigenic peptides, especially in synergy with the CD8 co-receptor. Both TCR affinity and target selection will influence potential safety issues. We suggest pre-clinical strategies that might be used to examine each TCR for possible on-target and off-target side effects due to self-reactivities, and to adjust TCR affinities accordingly.

  5. Interleukin 4: signalling mechanisms and control of T cell differentiation.

    Science.gov (United States)

    Paul, W E

    1997-01-01

    Interleukin 4 (IL-4) is a pleiotropic type I cytokine that controls both growth and differentiation among haemopoietic and non-haemopoietic cells. Its receptor is a heterodimer. One chain, the IL-4R alpha chain, binds IL-4 with high affinity and determines the nature of the biochemical signals that are induced. The second chain, gamma c, is required for the induction of such signals. IL-4-mediated growth depends upon activation events that involve phosphorylation of Y497 of IL-4R alpha, leading to the binding and phosphorylation of 4PS/IRS-2 in haemopoietic cells and of IRS-1 in non-haemopoietic cells. By contrast, IL-4-mediated differentiation events depend upon more distal regions of the IL-4R alpha chain that include a series of STAT-6 binding sites. The distinctive roles of these receptor domains was verified by receptor-reconstruction experiments. The 'growth' and 'differentiation' domains of the IL-4R alpha chain, independently expressed as chimeric structures with a truncated version of the IL-2R beta chain, were shown to convey their functions to the hybrid receptor. The critical role of STAT-6 in IL-4-mediated gene activation and differentiation was made clear by the finding that lymphocytes from STAT-6 knockout mice are strikingly deficient in these functions but have retained the capacity to grow, at least partially, in response to IL-4. IL-4 plays a central role in determining the phenotype of naive CD4+ T cells. In the presence of IL-4, newly primed naive T cells develop into IL-4 producers while in its absence they preferentially become gamma-interferon (IFN-gamma) producers. Recently, a specialized subpopulation of T cells, CD4+/NK1.1+ cells, has been shown to produce large amounts of IL-4 upon stimulation. Two examples of mice with deficiencies in these cells are described--beta 2-microglobulin knockout mice and SJL mice. Both show defects in the development of IL-4-producing cells and in the increase in serum IgE in response to stimulation with the

  6. T cell avidity and tumor recognition: implications and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Roszkowski Jeffrey J

    2005-09-01

    Full Text Available Abstract In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

  7. Metabolism, migration and memory in cytotoxic T cells.

    Science.gov (United States)

    Finlay, David; Cantrell, Doreen A

    2011-02-01

    The transcriptional and metabolic programmes that control CD8(+) T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8(+) T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine the effector versus memory fate of CD8(+) T cells. We speculate that one link between metabolism and immunological memory is provided by kinases that originally evolved to control T cell metabolism and have subsequently acquired the ability to control the expression of key transcription factors that regulate CD8(+) T cell effector function and migratory capacity.

  8. Adoptive T cell therapy targeting CD1 and MR1

    Directory of Open Access Journals (Sweden)

    Tingxi eGuo

    2015-05-01

    Full Text Available Adoptive T cell immunotherapy has demonstrated clinically relevant efficacy in treating malignant and infectious diseases. However, much of these therapies have been focused on enhancing, or generating de novo, effector functions of conventional T cells recognizing HLA molecules. Given the heterogeneity of HLA alleles, mismatched patients are ineligible for current HLA-restricted adoptive T cell therapies. CD1 and MR1 are class I-like monomorphic molecules and their restricted T cells possess unique T cell receptor specificity against entirely different classes of antigens. CD1 and MR1 molecules present lipid and vitamin B metabolite antigens, respectively, and offer a new front of targets for T cell therapies. This review will cover the recent progress in the basic research of CD1, MR1, and their restricted T cells that possess translational potential.

  9. T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

    Science.gov (United States)

    Singh, Nathan; Kulikovskaya, Irina; Barrett, David M; Binder-Scholl, Gwendolyn; Jakobsen, Bent; Martinez, Daniel; Pawel, Bruce; June, Carl H; Kalos, Michael D; Grupp, Stephan A

    The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro , we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma.

  10. Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets.

    Science.gov (United States)

    Ryan, John F; Hovde, Rachel; Glanville, Jacob; Lyu, Shu-Chen; Ji, Xuhuai; Gupta, Sheena; Tibshirani, Robert J; Jay, David C; Boyd, Scott D; Chinthrajah, R Sharon; Davis, Mark M; Galli, Stephen J; Maecker, Holden T; Nadeau, Kari C

    2016-03-01

    Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.

  11. The Affinity of Elongated Membrane-Tethered Ligands Determines Potency of T Cell Receptor Triggering

    Directory of Open Access Journals (Sweden)

    Bing-Mae Chen

    2017-07-01

    Full Text Available T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11 in addition to recombinant class I and II pMHC molecules. The dimensions of membrane-tethered anti-CD3 and pMHC molecules were progressively increased by insertion of different extracellular domains. In agreement with previous studies, elongation of pMHC molecules or low-affinity anti-CD3 scFv caused progressive loss of T cell activation. However, elongation of high-affinity ligands (BC3 and OKT3 scFv did not abolish TCR phosphorylation and T cell activation. Mutation of key amino acids in OKT3 to reduce binding affinity to CD3 resulted in restoration of topological dependence on T cell activation. Our results show that high-affinity TCR ligands can effectively induce TCR triggering even at large interspatial distances between T cells and APCs.

  12. Developmental heterogeneity in DNA packaging patterns influences T-cell activation and transmigration.

    Directory of Open Access Journals (Sweden)

    Soumya Gupta

    Full Text Available Cellular differentiation programs are accompanied by large-scale changes in nuclear organization and gene expression. In this context, accompanying transitions in chromatin assembly that facilitates changes in gene expression and cell behavior in a developmental system are poorly understood. Here, we address this gap and map structural changes in chromatin organization during murine T-cell development, to describe an unusual heterogeneity in chromatin organization and associated functional correlates in T-cell lineage. Confocal imaging of DNA assembly in cells isolated from bone marrow, thymus and spleen reveal the emergence of heterogeneous patterns in DNA organization in mature T-cells following their exit from the thymus. The central DNA pattern dominated in immature precursor cells in the thymus whereas both central and peripheral DNA patterns were observed in naïve and memory cells in circulation. Naïve T-cells with central DNA patterns exhibited higher mechanical pliability in response to compressive loads in vitro and transmigration assays in vivo, and demonstrated accelerated expression of activation-induced marker CD69. T-cell activation was characterized by marked redistribution of DNA assembly to a central DNA pattern and increased nuclear size. Notably, heterogeneity in DNA patterns recovered in cells induced into quiescence in culture, suggesting an internal regulatory mechanism for chromatin reorganization. Taken together, our results uncover an important component of plasticity in nuclear organization, reflected in chromatin assembly, during T-cell development, differentiation and transmigration.

  13. The Dendritic Cell Synapse: A Life Dedicated to T Cell Activation.

    Science.gov (United States)

    Benvenuti, Federica

    2016-01-01

    T-cell activation within immunological synapses is a complex process whereby different types of signals are transmitted from antigen-presenting cells to T cells. The molecular strategies developed by T cells to interpret and integrate these signals have been systematically dissected in recent years and are now in large part understood. On the other side of the immune synapse, dendritic cells (DCs) participate actively in synapse formation and maintenance by remodeling of membrane receptors and intracellular content. However, the details of such changes have been only partially characterized. The DCs actin cytoskeleton has been one of the first systems to be identified as playing an important role in T-cell priming and some of the underlying mechanisms have been elucidated. Similarly, the DCs microtubule cytoskeleton undergoes major spatial changes during synapse formation that favor polarization of the DCs subcellular space toward the interacting T cell. Recently, we have begun to investigate the trafficking machinery that controls polarized delivery of endosomal vesicles at the DC-T immune synapse with the aim of understanding the functional relevance of polarized secretion of soluble factors during T-cell priming. Here, we will review the current knowledge of events occurring in DCs during synapse formation and discuss the open questions that still remain unanswered.

  14. Herpes Simplex Virus Type 1 Infection of Activated Cytotoxic T Cells

    Science.gov (United States)

    Raftery, Martin J.; Behrens, Christian K.; Müller, Anke; Krammer, Peter H.; Walczak, Henning; Schönrich, Günther

    1999-01-01

    Herpes simplex virus type 1 (HSV1), a large DNA-containing virus, is endemic in all human populations investigated. After infection of mucocutaneous surfaces, HSV1 establishes a latent infection in nerve cells. Recently, it was demonstrated that HSV1 can also infect activated T lymphocytes. However, the consequences of T cell infection for viral pathogenesis and immunity are unknown. We have observed that in contrast to the situation in human fibroblasts, in human T cell lines antigen presentation by major histocompatibility complex class I molecules is not blocked after HSV1 infection. Moreover, HSV1 infection of T cells results in rapid elimination of antiviral T cells by fratricide. To dissect the underlying molecular events, we used a transgenic mouse model of HSV1 infection to demonstrate that CD95 (Apo-1, Fas)-triggered apoptosis is essential for HSV1-induced fratricide, whereas tumor necrosis factor (TNF) also contributes to this phenomenon but to a lesser extent. By contrast, neither TRAIL (TNF-related apoptosis-inducing ligand) nor perforin were involved. Finally, we defined two mechanisms associated with HSV1-associated fratricide of antiviral T cells: (a) T cell receptor–mediated upregulation of CD95 ligand and (b) a viral “competence-to-die” signal that renders activated T lymphocytes susceptible to CD95 signaling. We propose that induction of fratricide is an important immune evasion mechanism of HSV1, helping the virus to persist in the host organism throughout its lifetime. PMID:10523608

  15. Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

    DEFF Research Database (Denmark)

    Zeka, Bleranda; Hastermann, Maria; Hochmeister, Sonja

    2015-01-01

    NMO lesions contain activated CD4(+) T cells, the question arose whether AQP4-specific T cells might not only provide T cell help for antibody production, but also play an important role in the induction of NMO lesions. We show here that highly pathogenic, AQP4-peptide-specific T cells exist in Lewis...... remarkably, together with NMO-IgG, they initiate large astrocyte-destructive lesions which are located predominantly in spinal cord gray matter. We conclude that the processing of AQP4 by antigen presenting cells in Lewis rats produces a highly encephalitogenic AQP4 epitope (AQP4268-285), that T cells...

  16. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers.

    Science.gov (United States)

    Palma, Marzia; Gentilcore, Giusy; Heimersson, Kia; Mozaffari, Fariba; Näsman-Glaser, Barbro; Young, Emma; Rosenquist, Richard; Hansson, Lotta; Österborg, Anders; Mellstedt, Håkan

    2017-03-01

    Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3 + cells and the CD8 + subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4 + and CD8 + cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients ( P =0.0003 and P =0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4 + and CD8 + subsets, with a significantly higher PD-1 expression. Higher numbers of CD4 + and CD8 + cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67 + ) and activated (CD69 + ) CD4 + and CD8 + cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls ( P leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways. Copyright© Ferrata Storti Foundation.

  17. Identification of class I HLA T cell control epitopes for West Nile virus.

    Directory of Open Access Journals (Sweden)

    Saghar Kaabinejadian

    Full Text Available The recent West Nile virus (WNV outbreak in the United States underscores the importance of understanding human immune responses to this pathogen. Via the presentation of viral peptide ligands at the cell surface, class I HLA mediate the T cell recognition and killing of WNV infected cells. At this time, there are two key unknowns in regards to understanding protective T cell immunity: 1 the number of viral ligands presented by the HLA of infected cells, and 2 the distribution of T cell responses to these available HLA/viral complexes. Here, comparative mass spectroscopy was applied to determine the number of WNV peptides presented by the HLA-A*11:01 of infected cells after which T cell responses to these HLA/WNV complexes were assessed. Six viral peptides derived from capsid, NS3, NS4b, and NS5 were presented. When T cells from infected individuals were tested for reactivity to these six viral ligands, polyfunctional T cells were focused on the GTL9 WNV capsid peptide, ligands from NS3, NS4b, and NS5 were less immunogenic, and two ligands were largely inert, demonstrating that class I HLA reduce the WNV polyprotein to a handful of immune targets and that polyfunctional T cells recognize infections by zeroing in on particular HLA/WNV epitopes. Such dominant HLA/peptide epitopes are poised to drive the development of WNV vaccines that elicit protective T cells as well as providing key antigens for immunoassays that establish correlates of viral immunity.

  18. To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses.

    Directory of Open Access Journals (Sweden)

    Rafik Terra

    Full Text Available Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6 was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1 in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2 STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3 STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.

  19. Is psoriasis a T-cell disease?

    Science.gov (United States)

    Nickoloff, B J; Schröder, J M; von den Driesch, P; Raychaudhuri, S P; Farber, E M; Boehncke, W H; Morhenn, V B; Rosenberg, E W; Schön, M P; Holick, M F

    2000-10-01

    The etiology and pathogenesis of psoriasis--one of the most common chronic, inflammatory, hyperproliferative skin disorders of man--have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal-mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom infatuated with a T-cell-centered approach to inflammatory skin diseases-- portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative "pockets of academic resistance" are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

  20. Regulatory T Cells in Radiotherapeutic Responses

    International Nuclear Information System (INIS)

    Schaue, Dörthe; Xie, Michael W.; Ratikan, Josephine A.; McBride, William H.

    2012-01-01

    Radiation therapy (RT) can extend its influence in cancer therapy beyond what can be attributed to in-field cytotoxicity by modulating the immune system. While complex, these systemic effects can help tip the therapeutic balance in favor of treatment success or failure. Engagement of the immune system is generally through recognition of damage-associated molecules expressed or released as a result of tumor and normal tissue radiation damage. This system has evolved to discriminate pathological from physiological forms of cell death by signaling “danger.” The multiple mechanisms that can be evoked include a shift toward a pro-inflammatory, pro-oxidant microenvironment that can promote maturation of dendritic cells and, in cancer treatment, the development of effector T cell responses to tumor-associated antigens. Control over these processes is exerted by regulatory T cells (Tregs), suppressor macrophages, and immunosuppressive cytokines that act in consort to maintain tolerance to self, limit tissue damage, and re-establish tissue homeostasis. Unfortunately, by the time RT for cancer is initiated the tumor-host relationship has already been sculpted in favor of tumor growth and against immune-mediated mechanisms for tumor regression. Reversing this situation is a major challenge. However, recent data show that removal of Tregs can tip the balance in favor of the generation of radiation-induced anti-tumor immunity. The clinical challenge is to do so without excessive depletion that might precipitate serious autoimmune reactions and increase the likelihood of normal tissue complications. The selective modulation of Treg biology to maintain immune tolerance and control of normal tissue damage, while releasing the “brakes” on anti-tumor immune responses, is a worthy aim with promise for enhancing the therapeutic benefit of RT for cancer.

  1. Regulatory T cells in radiotherapeutic responses

    Directory of Open Access Journals (Sweden)

    Dörthe eSchaue

    2012-08-01

    Full Text Available Radiation therapy (RT can extend its influence in cancer therapy beyond what can be attributed to in-field cytotoxicity by modulating the immune system. While complex, these systemic effects can help tip the therapeutic balance in favor of treatment success or failure. Engagement of the immune system is generally through recognition of damage-associated molecules expressed or released as a result of tumor and normal tissue radiation damage. This system has evolved to discriminate pathological from physiological forms of cell death by signaling danger. The multiple mechanisms that can be evoked include a shift towards a pro-inflammatory, pro-oxidant microenvironment that can promote maturation of dendritic cells and, in cancer treatment, the development of effector T cell responses to tumor-associated antigens. Control over these processes is exerted by regulatory T cells (Tregs, suppressor macrophages and immunosuppressive cytokines that act in consort to maintain tolerance to self, limit tissue damage, and re-establish tissue homeostasis. Unfortunately, by the time RT for cancer is initiated the tumor-host relationship has already been sculpted in favor of tumor growth and against immune-mediated mechanisms for tumor regression. Reversing this situation is a major challenge. However, recent data show that removal of Tregs can tip the balance in favor of the generation of radiation-induced anti-tumor immunity. The clinical challenge is to do so without excessive depletion that might precipitate serious autoimmune reactions and increase the likelihood of normal tissue complications. The selective modulation of Treg biology to maintain immune tolerance and control of normal tissue damage, while releasing the brakes on anti-tumor immune responses, is a worthy aim with promise for enhancing the therapeutic benefit of RT for cancer.

  2. Cytomegalovirus infection: a driving force in human T cell immunosenescence.

    Science.gov (United States)

    Koch, Sven; Larbi, Anis; Ozcelik, Dennis; Solana, Rafael; Gouttefangeas, Cécile; Attig, Sebastian; Wikby, Anders; Strindhall, Jan; Franceschi, Claudio; Pawelec, Graham

    2007-10-01

    The human immune system evolved to defend the organism against pathogens, but is clearly less well able to do so in the elderly, resulting in greater morbidity and mortality due to infectious disease in old people, and higher healthcare costs. Many age-associated immune alterations have been reported over the years, of which probably the changes in T cell immunity, often manifested dramatically as large clonal expansions of cells of limited antigen specificity together with a marked shrinkage of the T cell antigen receptor repertoire, are the most notable. It has recently emerged that the common herpesvirus, cytomegalovirus (CMV), which establishes persistent, life-long infection, usually asymptomatically, may well be the driving force behind clonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. In those few who are not CMV-infected, another even more common herpesvirus, the Epstein-Barr virus, appears to have the same effect. These virus-driven changes are less marked in "successfully aged" centenarians, but most marked in people whom longitudinal studies have shown to be at higher risk of death, that is, those possessing an "immune risk profile" (IRP) characterized by an inverted CD4:8 ratio (caused by the accumulation primarily of CD8(+) CD28(-) cells). These findings support the hypothesis that persistent herpesviruses, especially CMV, act as chronic antigenic stressors and play a major causative role in immunosenescence and associated mortality.

  3. TGF-beta and 'adaptive' Foxp3(+) regulatory T cells.

    Science.gov (United States)

    Chen, Wanjun; Konkel, Joanne E

    2010-02-01

    In naïve T cells transforming growth factor-beta (TGF-beta) induces Foxp3, a transcription factor essential for programming and developing T regulatory cells (Treg cells). This finding reveals a physiological factor which can turn on the Foxp3 gene and establishes an experimental approach to induce antigen-specific Treg cells as a potential therapy for human diseases. While this role for TGF-beta is well confirmed, several critical questions remain largely unanswered and await further investigation. In this regard, it is imperative to understand the molecular pathways by which TGF-beta signaling initiates and regulates Foxp3 expression. It is also important to elucidate which factors and/or cytokines influence the TGF-beta-mediated conversion of naïve T cells and how to create an immunologically regulatory milieu to facilitate Treg cell generation in vivo. In this short article, we will highlight the key findings and recent progress in the field, discuss the molecular mechanisms underlying the TGF-beta-mediated induction of Foxp3, and attempt to outline the challenges ahead.

  4. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance

    Science.gov (United States)

    Ye, B; Liu, X; Li, X; Kong, H; Tian, L; Chen, Y

    2015-01-01

    Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the ‘exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4+ and CD8+ T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8+ T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options

  5. Cholecalciferol in Improving Survival in Patients With Newly Diagnosed Cancer With Vitamin D Insufficiency

    Science.gov (United States)

    2017-07-06

    Aggressive Non-Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-Cell Lymphoma; Enteropathy-Associated T-Cell Lymphoma; Hepatosplenic T-Cell Lymphoma; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Nasal Type Extranodal NK/T-Cell Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified; Primary Cutaneous Anaplastic Large Cell Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Small Lymphocytic Lymphoma; Subcutaneous Panniculitis-Like T-Cell Lymphoma

  6. Liposome-Coupled Peptides Induce Long-Lived Memory CD8+ T Cells Without CD4+ T Cells

    OpenAIRE

    Taneichi, Maiko; Tanaka, Yuriko; Kakiuchi, Terutaka; Uchida, Tetsuya

    2010-01-01

    CD8(+) T cells provide broad immunity to viruses, because they are able to recognize all types of viral proteins. Therefore, the development of vaccines capable of inducing long-lived memory CD8(+) T cells is desired to prevent diseases, especially those for which no vaccines currently exist. However, in designing CD8(+) T cell vaccines, the role of CD4(+) T cells in the induction and maintenance of memory CD8(+) T cells remains uncertain. In the present study, the necessity or not of CD4(+) ...

  7. Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy.

    Directory of Open Access Journals (Sweden)

    Elena Crespo

    Full Text Available Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90, to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67. We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction

  8. Involvement of the Fas/Fas ligand pathway in activation-induced cell death of mycobacteria-reactive human gamma delta T cells: a mechanism for the loss of gamma delta T cells in patients with pulmonary tuberculosis.

    Science.gov (United States)

    Li, B; Bassiri, H; Rossman, M D; Kramer, P; Eyuboglu, A F; Torres, M; Sada, E; Imir, T; Carding, S R

    1998-08-01

    Although the identity of T cells involved in the protection against Mycobacterium tuberculosis (Mtb) in humans remain unknown, patients with pulmonary tuberculosis (TB) have reduced numbers of Mtb-reactive, V gamma 9+/V delta 2+ T cells in their blood and lungs. Here we have determined whether this gamma deltaT loss is a consequence of Mtb Ag-mediated activation-induced cell death (AICD). Using a DNA polymerase-mediated dUTP nick translation labeling assay, 5% or less of freshly isolated CD4+ alpha beta or gamma delta T cells from normal healthy individuals and TB patients were apoptotic. However, during culture Mtb Ags induced apoptosis in a large proportion of V gamma 9+V delta 2+ peripheral blood T cells from healthy subjects (30-45%) and TB patients (55-68%); this was increased further in the presence of IL-2. By contrast, anti-CD3 did not induce any significant level of apoptosis in gamma delta T cells from healthy subjects or TB patients. Mtb Ag stimulation rapidly induced Fas and Fas ligand (FasL) expression by gamma delta T cells, and in the presence of metalloproteinase-inhibitors >70% of gamma delta T cells were FasL+. Blockade of Fas-FasL interactions reduced the level of Mtb-mediated gamma delta T cell apoptosis by 75 to 80%. Collectively, these findings demonstrate that Mtb-reactive gamma delta T cells are more susceptible to AICD and that the Fas-FasL pathways of apoptosis is involved. AICD of gamma delta T cells, therefore, provides an explanation for the loss of Mtb-reactive T cells during mycobacterial infection.

  9. CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection.

    Science.gov (United States)

    Linterman, Michelle A; Denton, Alice E; Divekar, Devina P; Zvetkova, Ilona; Kane, Leanne; Ferreira, Cristina; Veldhoen, Marc; Clare, Simon; Dougan, Gordon; Espéli, Marion; Smith, Kenneth G C

    2014-10-27

    The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4(+) T cells after priming. We show that continued CD28 expression is important for effector CD4(+) T cells following infection; maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming.

  10. Radiographically Negative, Asymptomatic, Sentinel Lymph Node Positive Cutaneous T-Cell Lymphoma in a 3-Year-Old Male: A Case Report

    Directory of Open Access Journals (Sweden)

    Jeffrey Carson

    2012-01-01

    Full Text Available We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

  11. A gut-homing, oligoclonal CD4+ T cell population in severe-combined immunodeficient mice expressing a rearranged, transgenic class I-restricted alpha beta T cell receptor

    DEFF Research Database (Denmark)

    Reimann, J; Rudolphi, A; Spiess, S

    1995-01-01

    We studied the peripheral T cell compartment of H-2b severe combined immunodeficient (scid) mice that express a transgenic (tg) alpha beta T cell receptor (TcR) specific for the H-Y (male) epitope presented by the H-2 class I Db molecule. Large populations of CD3+ NK1.1-TCR beta T+ T cells were......R alpha T-beta T+ cells were found in gut tissues of the immunodeficient host. Transplanted scid mice developed clinical and histological signs of IBD. An oligoclonal, gut-homing, memory/effector CD4+ CD44+ TcR beta T+ TcR alpha T-T cell subset from leaky tg scid mice thus has a pathogenic potential when...

  12. Thymopoiesis and regulatory T cells in healthy children and adolescents

    Directory of Open Access Journals (Sweden)

    Maria Izabel Arismendi

    2012-01-01

    Full Text Available OBJECTIVES: The purpose of this study was to investigate the association between T cell receptor excision circle levels in peripheral blood mononuclear cells and regulatory T cells that co-express CD25 and Foxp3 in healthy children and adolescents of different ages. MATERIALS AND METHODS: The quantification of signal-joint T-cell receptor excision circle levels in the genomic DNA of peripheral blood mononuclear cells was performed using real-time quantitative PCR. The analysis of CD4, CD8, CD25, and Foxp3 expression was performed using flow cytometry. RESULTS: Ninety-five healthy controls (46 females and 49 males ranging in age from 1 to 18 years were analyzed. The mean T-cell receptor excision circle count in all individuals was 89.095¡36.790 T-cell receptor excision circles per microgram of DNA. There was an inverse correlation between T-cell receptor excision circles counts and age (r = -0.846; p<0.001 as well as between the proportion of CD4+CD25+Foxp3+ T cells and age (r = -0.467; p = 0.04. In addition, we observed a positive correlation between the amount of CD4+CD25+Foxp3+ T cells and the amount of Tcell receptor excision circles per microgram of DNA in individuals of all ages (r = -0.529; p = 0.02. CONCLUSIONS: In this study, we observed a decrease in the thymic function with age based on the fact that the level of T-cell receptor excision circles in the peripheral blood positively correlated with the proportion of regulatory T cells in healthy children and adolescents. These findings indicate that although T-cell receptor excision circles and regulatory T cells levels decrease with age, homeostasis of the immune system and relative regulatory T cells population levels are maintained in the peripheral blood.

  13. Suppression of T cell-induced osteoclast formation

    Energy Technology Data Exchange (ETDEWEB)

    Karieb, Sahar; Fox, Simon W., E-mail: Simon.fox@plymouth.ac.uk

    2013-07-12

    Highlights: •Genistein and coumestrol prevent activated T cell induced osteoclast formation. •Anti-TNF neutralising antibodies prevent the pro-osteoclastic effect of activated T cells. •Phytoestrogens inhibit T cell derived TNF alpha and inflammatory cytokine production. •Phytoestrogens have a broader range of anti-osteoclastic actions than other anti-resorptives. -- Abstract: Inhibition of T cell derived cytokine production could help suppress osteoclast differentiation in inflammatory skeletal disorders. Bisphosphonates are typically prescribed to prevent inflammatory bone loss but are not tolerated by all patients and are associated with an increased risk of osteonecrosis of the jaw. In light of this other anti-resorptives such as phytoestrogens are being considered. However the effect of phytoestrogens on T cell-induced osteoclast formation is unclear. The effect of genistein and coumestrol on activated T cell-induced osteoclastogenesis and cytokine production was therefore examined. Concentrations of genistein and coumestrol (10{sup −7} M) previously shown to directly inhibit osteoclast formation also suppressed the formation of TRAP positive osteoclast induced by con A activated T cells, which was dependent on inhibition of T cell derived TNF-α. While both reduced osteoclast formation their mechanism of action differed. The anti-osteoclastic effect of coumestrol was associated with a dual effect on con A induced T cell proliferation and activation; 10{sup −7} M coumestrol significantly reducing T cell number (0.36) and TNF-α (0.47), IL-1β (0.23) and IL-6 (0.35) expression, whereas genistein (10{sup −7} M) had no effect on T cell number but a more pronounced effect on T cell differentiation reducing expression of TNF-α (0.49), IL-1β (0.52), IL-6 (0.71) and RANKL (0.71). Phytoestrogens therefore prevent the pro-osteoclastic action of T cells suggesting they may have a role in the control of inflammatory bone loss.

  14. In silico and cell-based analyses reveal strong divergence between prediction and observation of T-cell-recognized tumor antigen T-cell epitopes.

    Science.gov (United States)

    Schmidt, Julien; Guillaume, Philippe; Dojcinovic, Danijel; Karbach, Julia; Coukos, George; Luescher, Immanuel

    2017-07-14

    Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by in silico algorithms, but the predictive power of this approach is unclear. Here, we used the human tumor antigen NY-ESO-1 (ESO) and the human leukocyte antigen variant HLA-A*0201 (A2) as a model and predicted in silico the 41 highest-affinity, A2-binding 8-11-mer peptides and assessed their binding, kinetic complex stability, and immunogenicity in A2-transgenic mice and on peripheral blood mononuclear cells from ESO-vaccinated melanoma patients. We found that 19 of the peptides strongly bound to A2, 10 of which formed stable A2-peptide complexes and induced CD8 + T cells in A2-transgenic mice. However, only 5 of the peptides induced cognate T cells in humans; these peptides exhibited strong binding and complex stability and contained multiple large hydrophobic and aromatic amino acids. These results were not predicted by in silico algorithms and provide new clues to improving T-cell epitope identification. In conclusion, our findings indicate that only a small fraction of in silico -predicted A2-binding ESO peptides are immunogenic in humans, namely those that have high peptide-binding strength and complex stability. This observation highlights the need for improving in silico predictions of peptide immunogenicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Hyperoxia Inhibits T Cell Activation in Mice

    Science.gov (United States)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  16. Malignant T cells express lymphotoxin alpha and drive endothelial activation in cutaneous T cell lymphoma

    DEFF Research Database (Denmark)

    Lauenborg, Britt; Christensen, Louise; Ralfkiaer, Ulrik

    2015-01-01

    Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes...... to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating...... expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease....

  17. Holistic systems biology approaches to molecular mechanisms of human helper T cell differentiation to functionally distinct subsets.

    Science.gov (United States)

    Chen, Z; Lönnberg, T; Lahesmaa, R

    2013-08-01

    Current knowledge of helper T cell differentiation largely relies on data generated from mouse studies. To develop therapeutical strategies combating human diseases, understanding the molecular mechanisms how human naïve T cells differentiate to functionally distinct T helper (Th) subsets as well as studies on human differentiated Th cell subsets is particularly valuable. Systems biology approaches provide a holistic view of the processes of T helper differentiation, enable discovery of new factors and pathways involved and generation of new hypotheses to be tested to improve our understanding of human Th cell differentiation and immune-mediated diseases. Here, we summarize studies where high-throughput systems biology approaches have been exploited to human primary T cells. These studies reveal new factors and signalling pathways influencing T cell differentiation towards distinct subsets, important for immune regulation. Such information provides new insights into T cell biology and into targeting immune system for therapeutic interventions. © 2013 John Wiley & Sons Ltd.

  18. Nasal Extranodal Natural Killer/T Cell Lymphoma in a 69-Year Old Female: A Case Report

    Directory of Open Access Journals (Sweden)

    Duygu Mert, Mehmet Sinan Dal, Fazilet Duygu

    2016-09-01

    Full Text Available Mature natural killer /T-cell (NK/T-cell lymphomas are a rarely occurring subgroup of Non Hodgkin Lymphomas (NHL. A large majority of NK/T cell lymphomas are extranodal. Nasal type is the most common one. As clinical symptoms are usually nasal obstruction associated with mass lesion and epistaxis in extranodal NK/T cell lymphomas. Their diagnosis is usually delayed when the disease is advanced, it may have serious consequences. The aim of the present article was to present the clinical, radiological and histopathological findings of a 69-year old female patient who had refractory ulcerated wound on left side of nose and followed for soft tissue infection. It was diagnosed with extranodal NK/T cell lymphoma after deep biopsy was obtained from the lesion and to discuss this rare disease in view of literature data. J Microbiol Infect Dis 2016;6(3: 140-144

  19. Metronomic chemotherapy in anaplastic thyroid carcinoma: A potentially feasible alternative to therapeutic nihilism

    Directory of Open Access Journals (Sweden)

    Swaroop Revannasiddaiah

    2015-01-01

    Full Text Available Anaplastic thyroid carcinoma (ATC is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT, and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

  20. Metronomic chemotherapy in anaplastic thyroid carcinoma: a potentially feasible alternative to therapeutic nihilism.

    Science.gov (United States)

    Revannasiddaiah, Swaroop; Madabhavi, Irappa; Bodh, Anita; Thakur, Priyanka; Sharma, Mukesh

    2015-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

  1. Acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma of the thyroid: A complicated case.

    Science.gov (United States)

    Kanaya, Hiroaki; Konno, Wataru; Fukami, Satoru; Hirabayashi, Hideki; Haruna, Shin-ichi

    2014-12-01

    The fibrous variant of Hashimoto thyroiditis is uncommon, accounting for approximately 10% of all cases of Hashimoto thyroiditis. We report a case of this variant that behaved like a malignant neoplasm. The patient was a 69-year-old man who presented with a right-sided anterior neck mass that had been rapidly growing for 2 weeks. Fine-needle aspiration cytology revealed clusters of large multinucleated cells suggestive of an anaplastic carcinoma. A week after presentation, we ruled out that possibility when the mass had shrunk slightly. Instead, we diagnosed the patient with an acute exacerbation of Hashimoto thyroiditis on the basis of laboratory findings. We performed a right thyroid lobectomy, including removal of the isthmus, to clarify the pathology and alleviate pressure symptoms. The final diagnosis was the fibrous variant of Hashimoto thyroiditis, with no evidence of malignant changes. Physicians should keep in mind that on rare occasions, Hashimoto thyroiditis mimics a malignant neoplasm.

  2. Computational modeling of heterogeneity and function of CD4+ T cells

    Directory of Open Access Journals (Sweden)

    Adria eCarbo

    2014-07-01

    Full Text Available The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation.

  3. Increased sensitivity to interferon-alpha in psoriatic T cells

    DEFF Research Database (Denmark)

    Eriksen, Karsten Wessel; Lovato, Paola; Skov, Lone

    2005-01-01

    Psoriasis is a chronic inflammatory skin disease characterized by abnormal epidermal proliferation. Several studies have shown that skin-infiltrating activated T cells and cytokines play a pivotal role during the initiation and maintenance of the disease. Interferon (IFN)-alpha plays an important...... disease characterized by CD8(+)-infiltrating T cells. In this study, we therefore investigate IFN-alpha signaling in T cells isolated from involved skin of psoriatic patients. We show that psoriatic T cells have increased and prolonged responses to IFN-alpha, on the level of signal transducers...... and activators of transcription (STAT) activation, compared with infiltrating T cells from skin of non-psoriatic donors. Functionally, the increased IFN-alpha signaling leads to an increased binding of STAT4 to the IFN-gamma promotor, IFN-gamma production, and inhibition of T cell growth. In contrast, to STAT...

  4. CD4+/CD8+ double-positive T cells

    DEFF Research Database (Denmark)

    Overgaard, Nana H; Jung, Ji-Won; Steptoe, Raymond J

    2015-01-01

    CD4(+)/CD8(+) DP thymocytes are a well-described T cell developmental stage within the thymus. However, once differentiated, the CD4(+) lineage or the CD8(+) lineage is generally considered to be fixed. Nevertheless, mature CD4(+)/CD8(+) DP T cells have been described in the blood and peripheral...... cells, CD4(+)/CD8(+) T cell populations, outside of the thymus, have recently been described to express concurrently ThPOK and Runx3. Considerable heterogeneity exists within the CD4(+)/CD8(+) DP T cell pool, and the function of CD4(+)/CD8(+) T cell populations remains controversial, with conflicting...... reports describing cytotoxic or suppressive roles for these cells. In this review, we describe how transcriptional regulation, lineage of origin, heterogeneity of CD4 and CD8 expression, age, species, and specific disease settings influence the functionality of this rarely studied T cell population....

  5. Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

    Science.gov (United States)

    Provine, Nicholas M.; Larocca, Rafael A.; Aid, Malika; Penaloza-MacMaster, Pablo; Badamchi-Zadeh, Alexander; Borducchi, Erica N.; Yates, Kathleen B.; Abbink, Peter; Kirilova, Marinela; Ng’ang’a, David; Bramson, Jonathan; Haining, W. Nicholas

    2016-01-01

    CD4+ T cell help is critical for optimal CD8+ T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4+ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8+ T cell functionality and differentiation. Unhelped CD8+ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8+ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4+ T cell–deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4+ T cell help is required to promote both the expansion and acquisition of effector functions by CD8+ T cells, which is accomplished by preventing immediate dysfunction. PMID:27448585

  6. FRED--a framework for T-cell epitope detection.

    Science.gov (United States)

    Feldhahn, Magdalena; Dönnes, Pierre; Thiel, Philipp; Kohlbacher, Oliver

    2009-10-15

    Over the last decade, immunoinformatics has made significant progress. Computational approaches, in particular the prediction of T-cell epitopes using machine learning methods, are at the core of modern vaccine design. Large-scale analyses and the integration or comparison of different methods become increasingly important. We have developed FRED, an extendable, open source software framework for key tasks in immunoinformatics. In this, its first version, FRED offers easily accessible prediction methods for MHC binding and antigen processing as well as general infrastructure for the handling of antigen sequence data and epitopes. FRED is implemented in Python in a modular way and allows the integration of external methods. FRED is freely available for download at http://www-bs.informatik.uni-tuebingen.de/Software/FRED.

  7. Radiotherapy in anaplastic thyroid carcinoma: An Australian experience

    International Nuclear Information System (INIS)

    So, Kevin; Smith, Robin E.; Davis, Sidney R.

    2017-01-01

    Anaplastic thyroid cancer is a rare and fatal malignancy, associated with significant local tumour and often treatment related morbidity. We report our experience in treating this cancer over a 20-year period. A retrospective review of prospectively collected data from a single Australian Institution (Alfred Health Radiation Oncology) was carried out on patients referred with anaplastic thyroid carcinoma between 1992 and 2013. Thirty patients (17 females and 13 males) were identified with a median age at presentation of 72 years. At presentation, six (20%), 14 (47%) and 10 (33%) patients had stage IVA, IVB and IVC disease respectively. Thirteen patients underwent radical surgical resection with five having microscopic residual (R1) and eight having macroscopic residual (R2) disease. Twenty-eight patients were offered radiotherapy with 27 proceeding with treatment. Of those who received radiotherapy, three, six and 18 were treated with adjuvant, definitive and palliative intent respectively. Six patients had concomitant chemotherapy of which three received trimodality therapy. Only one patient experienced a grade 3 toxicity (oesophagitis). Median survival was 5.3 months and at last follow-up or time of death, 19 of 27 (70.4%) maintained loco-regional control. All patients who had R1 surgical resections and radiotherapy had loco-regional control. Seven of nine (77.8%) and 12 of 18 (66.7%) achieved loco-regional control after receiving definitive or palliative radiotherapy, respectively. Our study suggests that radiotherapy with or without surgery or chemotherapy is well-tolerated and results in durable loco-regional control in a high proportion of patients with anaplastic thyroid carcinoma.

  8. The effect of low level laser on anaplastic thyroid cancer

    Science.gov (United States)

    Rhee, Yun-Hee; Moon, Jeon-Hwan; Ahn, Jin-Chul; Chung, Phil-Sang

    2015-02-01

    Low-level laser therapy (LLLT) is a non-thermal phototherapy used in several medical applications, including wound healing, reduction of pain and amelioration of oral mucositis. Nevertheless, the effects of LLLT upon cancer or dysplastic cells have been so far poorly studied. Here we report that the effects of laser irradiation on anaplastic thyroid cancer cells leads to hyperplasia. 650nm of laser diode was performed with a different time interval (0, 15, 30, 60J/cm2 , 25mW) on anaplastic thyroid cancer cell line FRO in vivo. FRO was orthotopically injected into the thyroid gland of nude mice and the irradiation was performed with the same method described previously. After irradiation, the xenograft evaluation was followed for one month. The thyroid tissues from sacrificed mice were undergone to H&E staining and immunohistochemical staining with HIF-1α, Akt, TGF-β1. We found the aggressive proliferation of FRO on thyroid gland with dose dependent. In case of 60 J/ cm2 of energy density, the necrotic bodies were found in a center of the thyroid. The phosphorylation of HIF-1α and Akt was detected in the thyroid gland, which explained the survival signaling of anaplastic cancer cell was turned on the thyroid gland. Furthermore, TGF-β1 expression was decreased after irradiation. In this study, we demonstrated that insufficient energy density irradiation occurred the decreasing of TGF-β1 which corresponding to the phosphorylation of Akt/ HIF-1α. This aggressive proliferation resulted to the hypoxic condition of tissue for angiogenesis. We suggest that LLLT may influence to cancer aggressiveness associated with a decrease in TGF-β1 and increase in Akt/HIF-1α.

  9. T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.

    Directory of Open Access Journals (Sweden)

    Wai-Ping Fung-Leung

    Full Text Available Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers.

  10. Differentiation, distribution and gammadelta T cell-driven regulation of IL-22-producing T cells in tuberculosis.

    Directory of Open Access Journals (Sweden)

    Shuyu Yao

    2010-02-01

    Full Text Available Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vgamma2Vdelta2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNgamma-producing Vgamma2Vdelta2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNgamma neutralizing Ab treatment reversed the HMBPP-mediated down-regulation effect on IL-22-producing T cells, suggesting that Vgamma2Vdelta2 T-cell-driven IFNgamma-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vgamma2Vdelta2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB.

  11. Regulation of CD8+ T cell responses to retinal antigen by local FoxP3+ regulatory T cells

    Directory of Open Access Journals (Sweden)

    Scott W McPherson

    2012-06-01

    Full Text Available While pathogenic CD4 T cells are well known mediators of autoimmune uveoretinitis, CD8 T cells can also be uveitogenic. Since preliminary studies indicated that C57BL/6 mice were minimally susceptible to autoimmune uveoretinitis induction by CD8 T cells, the basis of the retinal disease resistance was sought. Mice that express β-galactosidase (βgal on a retina-specific promoter (arrβgal mice were backcrossed to mice expressing green fluorescent protein and diphtheria toxin receptor under control of the Foxp3 promoter (Foxp3-DTR/GFP mice, and to T cell receptor transgenic mice that produce βgal specific CD8 T cells (BG1 mice. These mice were used to explore the role of regulatory T cells in the resistance to retinal autoimmune disease. Experiments with T cells from double transgenic BG1 x Foxp3-DTR/GFP mice transferred into Foxp3-DTR/GFP x arrβgal mice confirmed that the retina was well protected from attempts to induce disease by adoptive transfer of activated BG1 T cells. The successful induction of retinal disease following unilateral intraocular administration of diphtheria toxin to deplete regulatory T cells showed that the protective activity was dependent on local, toxin-sensitive regulatory T cells; the opposite, untreated eye remained disease-free. Although there were very few Foxp3+ regulatory T cells in the parenchyma of quiescent retina, and they did not accumulate in retina, their depletion by local toxin administration led to disease susceptibility. We propose that these regulatory T cells modulate the pathogenic activity of βgal-specific CD8 T cells in the retinas of arrβgal mice on a local basis, allowing immunoregulation to be responsive to local conditions.

  12. The Different T-cell Receptor Repertoires in Breast Cancer Tumors, Draining Lymph Nodes, and Adjacent Tissues.

    Science.gov (United States)

    Wang, Ting; Wang, Changxi; Wu, Jinghua; He, Chenyang; Zhang, Wei; Liu, Jiayun; Zhang, Ruifang; Lv, Yonggang; Li, Yongping; Zeng, Xiaojing; Cao, Hongzhi; Zhang, Xiuqing; Xu, Xun; Huang, Chen; Wang, Ling; Liu, Xiao

    2017-02-01

    T lymphocytes infiltrate the microenvironment of breast cancer tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCR) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here, we have analyzed the TCR repertoire of T cells using multiplex PCR and high-throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph nodes of breast cancer patients. T-cell repertoire diversity in tumors was lower than in lymph nodes, but higher than in nontumor tissue, with a preferential use of variable and joining genes. These data are consistent with the hypothesis that most of the T cells in tumors derive from the lymph node, followed by their expansion in tumor tissue. Positive nodes appeared to enhance T-cell infiltration into tumors and T-cell clonal expansion in lymph nodes. Additionally, the similarity in TCR repertoire between tumor and nontumor tissue was significantly higher in luminal-like, rather than basal-like, breast cancer. Our study elucidated the high heterogeneity of the TCR repertoire and provides potential for future improvements in immune-related diagnosis, therapy, and prognosis for breast cancer patients. Cancer Immunol Res; 5(2); 148-56. ©2016 AACR. ©2016 American Association for Cancer Research.

  13. CD34-based enrichment of genetically engineered human T cells for clinical use results in dramatically enhanced tumor targeting.

    Science.gov (United States)

    Norell, Håkan; Zhang, Yi; McCracken, James; Martins da Palma, Telma; Lesher, Aaron; Liu, Yueying; Roszkowski, Jeffrey J; Temple, Anquanette; Callender, Glenda G; Clay, Timothy; Orentas, Rimas; Guevara-Patiño, José; Nishimura, Michael I

    2010-06-01

    Objective clinical responses can be achieved in melanoma patients by infusion of T cell receptor (TCR) gene transduced T cells. Although promising, the therapy is still largely ineffective, as most patients did not benefit from treatment. That only a minority of the infused T cells were genetically modified and that these were extensively expanded ex vivo may have prevented their efficacy. We developed novel and generally applicable retroviral vectors that allow rapid and efficient selection of T cells transduced with human TCRs. These vectors encode two TCR chains and a truncated CD34 molecule (CD34t) in a single mRNA transcript. Transduced T cells were characterized and the effects of CD34-based enrichment of redirected T cells were evaluated. Both CD8(+) and CD4(+) T cells could be transduced and efficiently co-expressed all introduced transgenes on their surface. Importantly, more than fivefold enrichment of both the frequency of transduced cells and the specific anti-tumor reactivity of the effector population could be achieved by magnetic beads-based enrichment procedures readily available for clinical grade hematopoietic stem cell isolation. This CD34-based enrichment technology will improve the feasibility of adoptive transfer of clinically relevant effectors. In addition to their enhanced tumor recognition, the enriched redirected T cells may also show superior reactivity and persistence in vivo due to the high purity of transduced cells and the shortened ex vivo culture.

  14. Anaplastic thyroid carcinoma with rhabdomyoblastic differentiation : A case report with a good clinical outcome

    NARCIS (Netherlands)

    Olthof, Marijke; Persoon, Adrienne C. M.; Plukker, John T. M.; van der Wal, Jacqueline E.; Links, Thera P.

    2008-01-01

    Anaplastic thyroid carcinoma is a rare and highly malignant disease. Usually, this type of tumor is irresectable, and almost all patients die within 1 year after diagnosis. We present a case of anaplastic thyroid carcinoma with rhabdomyoblastic differentiation and good therapeutic outcome. A

  15. Coaggregation of the T-cell receptor with CD4 and other T-cell surface molecules enhances T-cell activation

    DEFF Research Database (Denmark)

    Owens, T; Fazekas de St Groth, B; Miller, J F

    1987-01-01

    and the TCR to stabilize TCR complexes and so to enhance T-cell activation. A related but less specific accessory role for other T-cell surface molecules is also suggested. We propose that the cellular interaction that leads to physiological T-cell activation not only achieves TCR ligation but also promotes......The CD4 molecule, expressed by T cells restricted by class II major histocompatibility complex (MHC) molecules, is believed to play a role in T-cell activation. We have previously suggested that CD4 interacts with the T-cell receptor for antigen (TCR) and with class II MHC and that this dual...... interaction stabilizes the bond between the TCR and antigen in association with MHC. To investigate the contribution of CD4-TCR interaction, we have used the murine monoclonal anti-TCR V beta 8 antibody F23.1 to activate cloned T cells. Weak activation by soluble biotinylated F23.1 was markedly enhanced...

  16. Frequency patterns of T-cell exposed motifs in immunoglobulin heavy chain peptides presented by MHCs

    Directory of Open Access Journals (Sweden)

    Robert D. Bremel

    2014-10-01

    Full Text Available Immunoglobulins are highly diverse protein sequences that are processed and presented to T-cells by B-cells and other antigen presenting cells. We examined a large dataset of immunoglobulin heavy chain variable regions (IGHV to assess the diversity of T-cell exposed motifs (TCEM. TCEM comprise those amino acids in a MHC-bound peptide which face outwards, surrounded by the MHC histotope, and which engage the T-cell receptor. Within IGHV there is a distinct pattern of predicted MHC class II binding and a very high frequency of re-use of the TCEMs. The re-use frequency indicates that only a limited number of different cognate T-cells are required to engage many different clonal B-cells. The amino acids in each outward-facing TCEM are intercalated with the amino acids of inward-facing MHC groove-exposed motifs (GEM. Different GEM may have differing, allele-specific, MHC binding affinities. The intercalation of TCEM and GEM in a peptide allows for a vast combinatorial repertoire of epitopes, each eliciting a different response. Outcome of T-cell receptor binding is determined by overall signal strength, which is a function of the number of responding T-cells and the duration of engagement. Hence, the frequency of T-cell exposed motif re-use appears to be an important determinant of whether a T-cell response is stimulatory or suppressive. The frequency distribution of TCEMs implies that somatic hypermutation is followed by clonal expansion that develop along repeated pathways. The observations of TCEM and GEM derived from immunoglobulins suggest a relatively simple, yet powerful, mechanism to correlate T-cell polyspecificity, through re-use of TCEMs, with a very high degree of specificity achieved by combination with a diversity of GEMs. The frequency profile of TCEMs also points to an economical mechanism for maintaining T-cell memory, recall, and self-discrimination based on an endogenously generated profile of motifs.

  17. Expanded human blood-derived γδT cells display potent antigen-presentation functions

    Directory of Open Access Journals (Sweden)

    Mohd Wajid Ali Khan

    2014-07-01

    Full Text Available Cell-based immunotherapy strategies target tumors directly (via cytolytic effector cells or aim at mobilizing endogenous anti-tumor immunity. The latter approach includes dendritic cells (DC, most frequently in the form of in vitro cultured peripheral blood monocytes-derived DC. Human blood γδT cells are selective for a single class of non-peptide agonists (phosphoantigens and develop into potent antigen-presenting cells (APC, termed γδT-APC, within 1-3 days of in vitro culture. Availability of large numbers of γδT-APC would be advantageous for use as a novel cellular vaccine. We here report optimal γδT cell expansion (>107 cells/ml blood when peripheral blood mononuclear cells (PBMC from healthy individuals and melanoma patients were stimulated with zoledronate and then cultured for 14 days in the presence of IL-2 and IL-15, yielding γδT cell cultures of variable purity (77±21% and 56±26%, respectively. They resembled effector-memory αβT (TEM cells and retained full functionality as assessed by in vitro tumor cell killing as well as secretion of proinflammatory cytokines (IFNγ, TNFα and cell proliferation in response to stimulation with phosphoantigens. Importantly, day 14 γδT cells expressed numerous APC-related cell surface markers and, in agreement, displayed potent in vitro APC functions. Day 14 γδT cells from PBMC of patients with cancer were equally effective as their counterparts derived from blood of healthy individuals and triggered potent CD8+ αβT cell responses following processing and cross-presentation of simple (influenza M1 and complex (tuberculin purified protein derivative protein antigens. Of note, and in clear contrast to peripheral blood γδT cells, the ability of day 14 γδT cells to trigger antigen-specific αβT cell responses did not depend on re-stimulation. We conclude that day 14 γδT cell cultures provide a convenient source of autologous APC for use in immunotherapy of

  18. Regulatory T cells and immunity to pathogens.

    Science.gov (United States)

    Rouse, Barry T; Suvas, Susmit

    2007-09-01

    Immune responses to pathogens are modulated by one or more types of cells that perform a regulatory function. Some cells with this function, such as CD4+ Foxp3+ natural regulatory T cells (nTreg), pre-exist prior to infections whereas others may be induced as a consequence of infection (adaptive Treg). With pathogens that have a complex pathogenesis, multiple types of regulatory cells could influence the outcome. One major property of Treg is to help minimize collateral tissue damage that can occur during immune reactions to a chronic infection. The consequence is less damage to the host but in such situations the pathogen is likely to establish persistence. In some cases, a fine balance is established between Treg responses, effector components of immunity and the pathogen. Treg responses to pathogens may also act to hamper the efficacy of immune control. This review discusses these issues as well as the likely mechanisms by which various pathogens can signal the participation of Treg during infection.

  19. Regulatory T Cells in Allergy and Asthma

    Directory of Open Access Journals (Sweden)

    Elena Martín-Orozco

    2017-05-01

    Full Text Available The immune system’s correct functioning requires a sophisticated balance between responses to continuous microbial challenges and tolerance to harmless antigens, such as self-antigens, food antigens, commensal microbes, allergens, etc. When this equilibrium is altered, it can lead to inflammatory pathologies, tumor growth, autoimmune disorders, and allergy/asthma. The objective of this review is to show the existing data on the importance of regulatory T cells (Tregs on this balance and to underline how intrauterine and postnatal environmental exposures influence the maturation of the immune system in humans. Genetic and environmental factors during embryo development and/or early life will result in a proper or, conversely, inadequate immune maturation with either beneficial or deleterious effects on health. We have focused herein on Tregs as a reflection of the maturity of the immune system. We explain the types, origins, and the mechanisms of action of these cells, discussing their role in allergy and asthma predisposition. Understanding the importance of Tregs in counteracting dysregulated immunity would provide approaches to diminish asthma and other related diseases in infants.

  20. T-cell inhibitors for atopic dermatitis.

    Science.gov (United States)

    Tidwell, W James; Fowler, Joseph F

    2018-03-01

    The management of atopic dermatitis is changing with the development of novel biologic agents to target specific molecules in the inflammatory cascade. Following the ability of dupilumab has proved its ability to act on the interleukin 4 receptor in treating atopic dermatitis. Thymic stromal lymphopoietin monoclonal antibody (AMG157/MEDI9929) and OX40 blocking antibody (GBR 830) were developed by targeting the same pathway as dupilumab further upstream. The clinical data on the efficacy for these drugs are not yet known. There is some early evidence that AMG157/MEDI9929 attenuates most measures of allergen-induced asthmatic responses. However, there are no public data on its ability to treat atopic dermatitis. In a phase 2a study, GBR 830 showed at least a 50% reduction in the Eczema Area and Severity Index scores of 17 of 23 patients, but it was not sufficiently powered for identification of statistical differences between GBR 830 versus placebo. Although there is potential for these 2 drugs to greatly improve the management of severe atopic dermatitis, significant clinical trials have not yet been completed to prove efficacy, and there are not yet any available phase 3 clinical trials, which are needed to truly evaluate their efficacy in affecting T-cells. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  1. Stimulation of adult oligodendrogenesis by myelin-specific T cells

    DEFF Research Database (Denmark)

    Hvilsted Nielsen, Helle; Toft-Hansen, Henrik; Lambertsen, Kate Lykke

    2011-01-01

    investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early...... of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system....

  2. T Cells in Gastric Cancer: Friends or Foes

    Science.gov (United States)

    Amedei, Amedeo; Della Bella, Chiara; Silvestri, Elena; Prisco, Domenico; D'Elios, Mario M.

    2012-01-01

    Gastric cancer is the second cause of cancer-related deaths worldwide. Helicobacter pylori is the major risk factor for gastric cancer. As for any type of cancer, T cells are crucial for recognition and elimination of gastric tumor cells. Unfortunately T cells, instead of protecting from the onset of cancer, can contribute to oncogenesis. Herein we review the different types, “friend or foe”, of T-cell response in gastric cancer. PMID:22693525

  3. Clinical trials of CAR-T cells in China

    OpenAIRE

    Bingshan Liu; Yongping Song; Delong Liu

    2017-01-01

    Abstract Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR)-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous...

  4. GM-CSF production allows the identification of immunoprevalent antigens recognized by human CD4+ T cells following smallpox vaccination.

    Directory of Open Access Journals (Sweden)

    Valeria Judkowski

    Full Text Available The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a "T cell-driven" methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens.

  5. Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naïve T cells into cytokine-producing mature T cells.

    Directory of Open Access Journals (Sweden)

    Kenshiro Tsuda

    Full Text Available T cells have been classified as belonging to the Th1 or Th2 subsets according to the production of defining cytokines such as IFN-γ and IL-4. The discovery of the Th17 lineage and regulatory T cells shifted the simple concept of the Th1/Th2 balance into a 4-way mechanistic pathway of local and systemic immunological activity. Clinically, the blockage of cytokine signals or non-specific suppression of cytokine predominance by immunosuppressants is the first-line treatment for inflammatory T cell-mediated disorders. Cyclosporine A (CsA and Tacrolimus (Tac are commonly used immunosuppressants for the treatment of autoimmune disease, psoriasis, and atopic disorders. Many studies have shown that these compounds suppress the activation of the calcium-dependent phosphatase calcineurin, thereby inhibiting T-cell activation. Although CsA and Tac are frequently utilized, their pharmacological mechanisms have not yet been fully elucidated.In the present study, we focused on the effects of CsA and Tac on cytokine secretion from purified human memory CD4(+T cells and the differentiation of naïve T cells into cytokine-producing memory T cells. CsA or Tac significantly inhibited IFN-γ, IL-4, and IL-17 production from memory T cells. These compounds also inhibited T cell differentiation into the Th1, Th2, and Th17 subsets, even when used at a low concentration. This study provided critical information regarding the clinical efficacies of CsA and Tac as immunosuppressants.

  6. T-cell exhaustion in allograft rejection and tolerance.

    Science.gov (United States)

    Thorp, Edward B; Stehlik, Christian; Ansari, M Javeed

    2015-02-01

    The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance.

  7. CD1 and mycobacterial lipids activate human T cells.

    Science.gov (United States)

    Van Rhijn, Ildiko; Moody, D Branch

    2015-03-01

    For decades, proteins were thought to be the sole or at least the dominant source of antigens for T cells. Studies in the 1990s demonstrated that CD1 proteins and mycobacterial lipids form specific targets of human αβ T cells. The molecular basis by which T-cell receptors (TCRs) recognize CD1-lipid complexes is now well understood. Many types of mycobacterial lipids function as antigens in the CD1 system, and new studies done with CD1 tetramers identify T-cell populations in the blood of tuberculosis patients. In human populations, a fundamental difference between the CD1 and major histocompatibility complex systems is that all humans express nearly identical CD1 proteins. Correspondingly, human CD1 responsive T cells show evidence of conserved TCRs. In addition to natural killer T cells and mucosal-associated invariant T (MAIT cells), conserved TCRs define other subsets of human T cells, including germline-encoded mycolyl-reactive (GEM) T cells. The simple immunogenetics of the CD1 system and new investigative tools to measure T-cell responses in humans now creates a situation in which known lipid antigens can be developed as immunodiagnostic and immunotherapeutic reagents for tuberculosis disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Metabolism, migration and memory in cytotoxic T cells

    OpenAIRE

    Finlay, David; Cantrell, Doreen

    2011-01-01

    The transcriptional and metabolic programs that control CD8+ T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8+ T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine...

  9. CD8 T cell persistence in treated HIV infection

    Science.gov (United States)

    Mudd, J. C.; Lederman, Michael M

    2014-01-01

    Purpose of review Many treated HIV infected persons maintain persistently high circulating CD8 T cell numbers, even after many years of therapy. Recent reports suggest that persistent CD8 T cell expansion is associated with higher risk of morbid non-AIDS events. Thus, assessing the mechanisms of CD8 T cell expansion and persistence may give insights into a feature of HIV disease that is clinically important. Recent findings Acute HIV infection is associated with activation and expansion of the CD8 T cell compartment. Expanded CD8 T cells persist throughout disease course and, in contrast to the plasticity that typically characterizes immune responses to most other pathogens, circulating CD8 T cell numbers do not normalize in many patients despite pharmacological suppression of HIV replication. We suspect that residual inflammation in treated HIV infection contributes to antigen-independent CD8 T cell expansion and persistence as most of these cells are not HIV-reactive. Summary Circulating CD8 T cell numbers remain abnormally elevated in many treated HIV-infected patients and this elevation is associated with adverse clinical events. Future studies will need to assess the mechanisms of CD8 T cell expansion and to define the role of CD8 lymphocytosis in the clinical course of treated HIV disease. PMID:25010897

  10. Chronic Inflammation and  T Cells

    Directory of Open Access Journals (Sweden)

    Nathan S Fay

    2016-05-01

    Full Text Available The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programmed to mobilize the host innate and adaptive immune responses. Included among these immune cells are  T cells that are unique in their TCR usage, location, and functions in the body. Stress reception by  T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces  T cell activation. Once activated,  T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon  T cell activation. Pathogenesis of many chronic inflammatory diseases involve  T cells; some of which are exacerbated by their presence, while others are improved.  T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial  T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts  T cell function. Future studies will be important to understand how this balance is achieved.

  11. Monoclonal T-cell receptors: new reagents for cancer therapy.

    Science.gov (United States)

    Stauss, Hans J; Cesco-Gaspere, Michela; Thomas, Sharyn; Hart, Daniel P; Xue, Shao-An; Holler, Angelika; Wright, Graham; Perro, Mario; Little, Ann-Margaret; Pospori, Constantina; King, Judy; Morris, Emma C

    2007-10-01

    Adoptive transfer of antigen-specific T lymphocytes is an effective form of immunotherapy for persistent virus infections and cancer. A major limitation of adoptive therapy is the inability to isolate antigen-specific T lymphocytes reproducibly. The demonstration that cloned T-cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. TCR gene-modified lymphocytes display antigen-specific function in vitro, and were shown to protect against virus infection and tumor growth in animal models. A recent trial in humans demonstrated that TCR gene-modified T cells persisted in all and reduced melanoma burden in 2/15 patients. In future trials, it may be possible to use TCR gene transfer to equip helper and cytotoxic T cells with new antigen-specificity, allowing both T-cell subsets to cooperate in achieving improved clinical responses. Sequence modifications of TCR genes are being explored to enhance TCR surface expression, while minimizing the risk of pairing between introduced and endogenous TCR chains. Current T-cell transduction protocols that trigger T-cell differentiation need to be modified to generate "undifferentiated" T cells, which, upon adoptive transfer, display improved in vivo expansion and survival. Both, expression of only the introduced TCR chains and the production of naïve T cells may be possible in the future by TCR gene transfer into stem cells.

  12. Tumor-derived exosomes induce CD8+T cell suppressors.

    Science.gov (United States)

    Maybruck, Brian T; Pfannenstiel, Lukas W; Diaz-Montero, Marcela; Gastman, Brian R

    2017-08-15

    The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8 + T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8 + T cells are tumor-derived exosomes (TDEs). Membrane vesicles and TDEs from multiple head and neck cancer cell line's conditioned growth media were isolated by ultracentrifugation and precipitation, respectively. Human purified CD3 + CD8 + T cells were assessed for their induction of the T cell SP by flow cytometry identifying loss of CD27/CD28 expression and in vitro suppression assays. Furthermore, the T cell SP was characterized for the attenuation of IFN-γ production. To delineate exosomal proteins contributing to T cell SP, mass spectrometry was used to identify unique proteins that were present in TDEs. CRISPR/Cas9 knockout constructs were used to examine the role of one of these proteins, galectin-1. To assess the role of exosomal RNA, RNA purified from TDEs was nucleofected into CD8 + T cells followed by suppression analysis. Using fractionated conditioned growth media, factors >200 kDa induced CD8 + T cell SP, which was determined to be an exosome by mass spectrometry analysis. Multiple head and neck cancer-derived cell lines were found to secrete T cell SP-inducing exosomes. Mass spectrometry analysis revealed that an immunoregulatory protein, galectin-1 (Gal-1), was expressed in those exosomes, but not in TDEs unable to induce T cell SP. Galectin-1 knockout cells were found to be less able to induce T cell SP. Furthermore, RNA purified from the T cell SP-inducing exosomes were found to partially induce the SP when transfected into normal CD8 + T cells. For the first-time, TDEs have been identified to induce a

  13. Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue.

    Science.gov (United States)

    Martinet, Kim Zita; Bloquet, Stéphane; Bourgeois, Christine

    2014-01-01

    CD4 T cell lymphopenia is an important T cell defect associated to ageing. Higher susceptibility to infections, cancer, or autoimmune pathologies described in aged individuals is thought to partly rely on T cell lymphopenia. We hypothesize that such diverse effects may reflect anatomical heterogeneity of age related T cell lymphopenia. Indeed, no data are currently available on the impact of ageing on T cell pool recovered from gut associated lymphoid tissue (GALT), a crucial site of CD4 T cell accumulation. Primary, secondary and tertiary lymphoid organs of C57BL/6 animals were analysed at three intervals of ages: 2 to 6 months (young), 10 to 14 months (middle-aged) and 22 to 26 months (old). We confirmed that ageing preferentially impacted CD4 T cell compartment in secondary lymphoid organs. Importantly, a different picture emerged from gut associated mucosal sites: during ageing, CD4 T cell accumulation was progressively developing in colon and small intestine lamina propria and Peyer's patches. Similar trend was also observed in middle-aged SJL/B6 F1 mice. Interestingly, an inverse correlation was detected between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria of C57BL/6 mice whereas no increase in proliferation rate of GALT CD4 T cells was detected. In contrast to GALT, no CD4 T cell accumulation was detected in lungs and liver in middle-aged animals. Finally, the concomitant accumulation of CD4 T cell in GALT and depletion in secondary lymphoid organs during ageing was detected both in male and female animals. Our data thus demonstrate that T cell lymphopenia in secondary lymphoid organs currently associated to ageing is not sustained in gut or lung mucosa associated lymphoid tissues or non-lymphoid sites such as the liver. The inverse correlation between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria and the absence of overt proliferation in GALT suggest that marked CD4 T cell decay in secondary

  14. Allergen and Epitope Targets of Mouse-Specific T Cell Responses in Allergy and Asthma

    Directory of Open Access Journals (Sweden)

    Véronique Schulten

    2018-02-01

    Full Text Available Mouse allergy has become increasingly common, mainly affecting laboratory workers and inner-city households. To date, only one major allergen, namely Mus m 1, has been described. We sought to identify T cell targets in mouse allergic patients. PBMC from allergic donors were expanded with either murine urine or epithelial extract and subsequently screened for cytokine production (IL-5 and IFNγ in response to overlapping peptides spanning the entire Mus m 1 sequence, peptides from various Mus m 1 isoforms [major urinary proteins (MUPs], peptides from mouse orthologs of known allergens from other mammalian species and peptides from proteins identified by immunoproteomic analysis of IgE/IgG immunoblots of mouse urine and epithelial extracts. This approach let to the identification of 106 non-redundant T cell epitopes derived from 35 antigens. Three major T cell-activating regions were defined in Mus m 1 alone. Moreover, our data show that immunodominant epitopes were largely shared between Mus m 1 and other MUPs even from different species, suggesting that sequence conservation in different allergens is a determinant for immunodominance. We further identified several novel mouse T cell antigens based on their homology to known mammalian allergens. Analysis of cohort-specific T cell responses revealed that rhinitis and asthmatic patients recognized different epitope repertoires. Epitopes defined herein can be formulated into an epitope “megapool” used to diagnose mouse allergy and study mouse-specific T cell responses directly ex vivo. This analysis of T cell epitopes provides a good basis for future studies to increase our understanding of the immunopathology associated with MO-allergy and asthma.

  15. Automated Manufacturing of Potent CD20-Directed Chimeric Antigen Receptor T Cells for Clinical Use.

    Science.gov (United States)

    Lock, Dominik; Mockel-Tenbrinck, Nadine; Drechsel, Katharina; Barth, Carola; Mauer, Daniela; Schaser, Thomas; Kolbe, Carolin; Al Rawashdeh, Wael; Brauner, Janina; Hardt, Olaf; Pflug, Natali; Holtick, Udo; Borchmann, Peter; Assenmacher, Mario; Kaiser, Andrew

    2017-10-01

    The clinical success of gene-engineered T cells expressing a chimeric antigen receptor (CAR), as manifested in several clinical trials for the treatment of B cell malignancies, warrants the development of a simple and robust manufacturing procedure capable of reducing to a minimum the challenges associated with its complexity. Conventional protocols comprise many open handling steps, are labor intensive, and are difficult to upscale for large numbers of patients. Furthermore, extensive training of personnel is required to avoid operator variations. An automated current Good Manufacturing Practice-compliant process has therefore been developed for the generation of gene-engineered T cells. Upon installation of the closed, single-use tubing set on the CliniMACS Prodigy™, sterile welding of the starting cell product, and sterile connection of the required reagents, T cells are magnetically enriched, stimulated, transduced using lentiviral vectors, expanded, and formulated. Starting from healthy donor (HD) or lymphoma or melanoma patient material (PM), the robustness and reproducibility of the manufacturing of anti-CD20 specific CAR T cells were verified. Independent of the starting material, operator, or device, the process consistently yielded a therapeutic dose of highly viable CAR T cells. Interestingly, the formulated product obtained with PM was comparable to that of HD with respect to cell composition, phenotype, and function, even though the starting material differed significantly. Potent antitumor reactivity of the produced anti-CD20 CAR T cells was shown in vitro as well as in vivo. In summary, the automated T cell transduction process meets the requirements for clinical manufacturing that the authors intend to use in two separate clinical trials for the treatment of melanoma and B cell lymphoma.

  16. Expression of the Tpl2/Cot oncogene in human T-cell neoplasias

    Science.gov (United States)

    Christoforidou, Anna V; Papadaki, Helen A; Margioris, Andrew N; Eliopoulos, George D; Tsatsanis, Christos

    2004-01-01

    Background Tpl2/Cot oncogene has been identified in murine T-cell lymphomas as a target of MoMuLV insertion. Animal and tissue culture studies have shown that Tpl2/Cot is involved in interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) production by T-cells contributing to T-cell proliferation. In the present report we examined a series of 12 adult patients with various T-cell malignancies, all with predominant leukemic expression in the periphery, for the expression of Tpl2/Cot oncogene in order to determine a possible involvement of Tpl2/Cot in the pathogenesis of these neoplasms. Results Our results showed that Tpl2/Cot was overexpressed in all four patients with Large Granular Lymphocyte proliferative disorders (LGL-PDs) but in none of the remaining eight patients with other T-cell neoplasias. Interestingly, three of the LGL-PD patients displayed neutropenia, one in association with sarcoidosis. Serum TNF-α levels were increased in all Tpl2/Cot overexpressing patients while serum IL-2 was undetectable in all subjects studied. Genomic DNA analysis revealed no DNA amplification at the Tpl2/Cot locus in any of the samples analyzed. Conclusions We conclude that Tpl2/Cot, a gene extensively studied in animal and tissue culture T-cell models may be also involved in the development of human LGL-PD and may have a role in the pathogenesis of immune manifestations associated with these diseases. This is the first report implicating Tpl2/Cot in human T-cell neoplasias and provides a novel molecular event in the development of LGL-PDs. PMID:15575964

  17. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins

    DEFF Research Database (Denmark)

    Woetmann, Anders; Lovato, Paola; Eriksen, Karsten W

    2007-01-01

    Bacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients....... The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant...... T cells enhance proliferation of the malignant cells in an SE- and MHC class II-dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4(+) T-cell lines also enhance proliferation of the malignant cells. The growth...

  18. CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis

    Science.gov (United States)

    McNally, Alice; Hill, Geoffrey R.; Sparwasser, Tim; Thomas, Ranjeny; Steptoe, Raymond J.

    2011-01-01

    CD4+CD25+ regulatory T cells (Treg) play a crucial role in the regulation of immune responses. Although many mechanisms of Treg suppression in vitro have been described, the mechanisms by which Treg modulate CD8+ T cell differentiation and effector function in vivo are more poorly defined. It has been proposed, in many instances, that modulation of cytokine homeostasis could be an important mechanism by which Treg regulate adaptive immunity; however, direct experimental evidence is sparse. Here we demonstrate that CD4+CD25+ Treg, by critically regulating IL-2 homeostasis, modulate CD8+ T-cell effector differentiation. Expansion and effector differentiation of CD8+ T cells is promoted by autocrine IL-2 but, by competing for IL-2, Treg limit CD8+ effector differentiation. Furthermore, a regulatory loop exists between Treg and CD8+ effector T cells, where IL-2 produced during CD8+ T-cell effector differentiation promotes Treg expansion. PMID:21502514

  19. CD 4 + CD 25 + T cells maintain homeostasis by promoting TER - 119 cell development and inhibiting T cell activation

    Directory of Open Access Journals (Sweden)

    Muhaimin Rifa’i

    2014-05-01

    Full Text Available CD4+ CD25+ regulatory T cells involved in the regulation of self- tolerance and normality of homeostasis. CD122 deficient mice are model animals that have an abnormal immune system characteristically have a high number of activated T cells and TER-119 cell decreased. Here we showed evidence that the transfer of CD4+ CD25+ regulatory T cells derived from normal mice to CD122- defficient neonates prevent the development of activated memory T cells and elicit TER-119 differentiation. Bone marrow reconstitution derived from CD122-/- mice to normal mice resulting tolerance to individual that genetically different. Importantly, CD4+ CD25+ regulatory T cells derived from normal mice can replace CD4+ CD25+ cells derived from CD122-/- mice. The results of this experiment suggest that regulatory T cells from normal mice exert a critical role in maintaining peripheral tolerance and controlling hematopoietic disorder.

  20. CD27 instructs CD4+ T cells to provide help for the memory CD8+ T cell response after protein immunization

    NARCIS (Netherlands)

    Xiao, Yanling; Peperzak, Victor; Keller, Anna M.; Borst, Jannie

    2008-01-01

    For optimal quality, memory CD8(+) T cells require CD4(+) T cell help. We have examined whether CD4(+) T cells require CD27 to deliver this help, in a model of intranasal OVA protein immunization. CD27 deficiency reduced the capacity of CD4(+) T cells to support Ag-specific CD8(+) T cell

  1. ZFAT plays critical roles in peripheral T cell homeostasis and its T cell receptor-mediated response

    Energy Technology Data Exchange (ETDEWEB)

    Doi, Keiko [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute of Life Sciences for the Next Generation of Women Scientists, Fukuoka University, Fukuoka (Japan); Fujimoto, Takahiro [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Okamura, Tadashi [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan); Ogawa, Masahiro [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Tanaka, Yoko [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Mototani, Yasumasa; Goto, Motohito [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan); Ota, Takeharu; Matsuzaki, Hiroshi [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Kuroki, Masahide [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Tsunoda, Toshiyuki [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Sasazuki, Takehiko [Institute for Advanced Study, Kyushu University, Fukuoka (Japan); Shirasawa, Senji, E-mail: sshirasa@fukuoka-u.ac.jp [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer We generated Cd4-Cre-mediated T cell-specific Zfat-deficient mice. Black-Right-Pointing-Pointer Zfat-deficiency leads to reduction in the number of the peripheral T cells. Black-Right-Pointing-Pointer Impaired T cell receptor-mediated response in Zfat-deficient peripheral T cells. Black-Right-Pointing-Pointer Decreased expression of IL-7R{alpha}, IL-2R{alpha} and IL-2 in Zfat-deficient peripheral T cells. Black-Right-Pointing-Pointer Zfat plays critical roles in peripheral T cell homeostasis. -- Abstract: ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in apoptosis, development and primitive hematopoiesis. Zfat is highly expressed in T- and B-cells in the lymphoid tissues, however, its physiological function in the immune system remains totally unknown. Here, we generated the T cell-specific Zfat-deficient mice and demonstrated that Zfat-deficiency leads to a remarkable reduction in the number of the peripheral T cells. Intriguingly, a reduced expression of IL-7R{alpha} and the impaired responsiveness to IL-7 for the survival were observed in the Zfat-deficient T cells. Furthermore, a severe defect in proliferation and increased apoptosis in the Zfat-deficient T cells following T cell receptor (TCR) stimulation was observed with a reduced IL-2R{alpha} expression as well as a reduced IL-2 production. Thus, our findings reveal that Zfat is a critical regulator in peripheral T cell homeostasis and its TCR-mediated response.

  2. Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T cell suppression in patients with rheumatoid arthritis.

    Science.gov (United States)

    Bonelli, Michael; Göschl, Lisa; Blüml, Stephan; Karonitsch, Thomas; Hirahara, Kiyoshi; Ferner, Elisabeth; Steiner, Carl-Walter; Steiner, Günter; Smolen, Josef S; Scheinecker, Clemens

    2016-04-01

    Abatacept (CTLA-4Ig) blocks CD28-mediated T cell activation by binding to the costimulatory B7 ligands CD80/CD86 on antigen presenting cells. Costimulatory molecules, however, can also be expressed on T cells upon activation. Therefore, the aim of our study was to investigate direct effects of CTLA-4Ig on distinct T cell subsets in RA patients. Phenotypic and functional analyses of CD4(+) T cells, including CD4(+) FoxP3(+) CD25(+) regulatory T cells (Treg), from RA patients were performed before and during CTLA-4Ig therapy. In addition T cells from healthy volunteers were analysed on in vitro culture with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Apoptotic DNA fragmentation in CD4(+) and CD4(+) FoxP3(+) T cells was measured by TUNEL staining. We observed an increase in T cells, including Treg cells, after initiation of CTLA-4Ig therapy, which was linked to a downregulation of activation-associated marker molecules and CD95 on CD4(+) T cells and Treg cells. CTLA-4Ig decreased CD95-mediated cell death in vitro in a dose-dependent manner. Functional analysis of isolated Treg cells from RA patients further revealed a diminished suppression of responder T cell proliferation. This was found to be due to CTLA-4Ig-mediated blocking of CD80 and CD86 on responder T cells that led to a diminished susceptibility for Treg cell suppression. CTLA-4Ig therapy in RA patients exerts effects beyond the suppression of T cell activation, which has to be taken into account as an additional mechanism of CTLA-4Ig treatment. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Polyfunctional CD4+ T Cells As Targets for Tuberculosis Vaccination

    Directory of Open Access Journals (Sweden)

    Deborah A. Lewinsohn

    2017-10-01

    Full Text Available Tuberculosis (TB, caused by Mycobacterium tuberculosis (Mtb, remains a leading cause of morbidity and mortality worldwide, despite the widespread use of the only licensed vaccine, Bacille Calmette Guerin (BCG. Eradication of TB will require a more effective vaccine, yet evaluation of new vaccine candidates is hampered by lack of defined correlates of protection. Animal and human studies of intracellular pathogens have extensively evaluated polyfunctional CD4+ T cells producing multiple pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2 as a possible correlate of protection from infection and disease. In this study, we review the published literature that evaluates whether or not BCG and/or novel TB vaccine candidates induce polyfunctional CD4+ T cells and if these T cell responses correlate with vaccine-mediated protection. Ample evidence suggests that BCG and several novel vaccine candidates evaluated in animal models and humans induce polyfunctional CD4+ T cells. However, while a number of studies utilizing the mouse TB model support that polyfunctional CD4+ T cells are associated with vaccine-induced protection, other studies in mouse and human infants demonstrate no correlation between these T cell responses and protection. We conclude that induction of polyfunctional CD4+ T cells is certainly not sufficient and may not even be necessary to mediate protection and suggest that other functional attributes, such as additional effector functions, T cell differentiation state, tissue homing potential, or long-term survival capacity of the T cell may be equally or more important to promote protection. Thus, a correlate of protection for TB vaccine development remains elusive. Future studies should address polyfunctional CD4+ T cells within the context of more comprehensive immunological signatures of protection that include other functions and phenotypes of T cells as well as the full spectrum of immune cells and mediators that participate in

  4. Human renal tubular epithelial cells suppress alloreactive T cell proliferation.

    Science.gov (United States)

    Demmers, M W H J; Korevaar, S S; Roemeling-van Rhijn, M; van den Bosch, T P P; Hoogduijn, M J; Betjes, M G H; Weimar, W; Baan, C C; Rowshani, A T

    2015-03-01

    Renal tubular epithelial cells (TECs) are one of the main targets of alloreactive T cells during acute rejection. We hypothesize that TECs modulate the outcome of alloimmunity by executing immunosuppressive effects in order to dampen the local inflammation. We studied whether TECs possess immunosuppressive capacities and if indoleamine 2,3-dioxygenase (IDO) might play a role in suppressing T cell alloreactivity. Next, we studied the role of programmed death ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1 with regard to TEC-related immunomodulatory effects. CD3/CD28 and alloactivated peripheral blood mononuclear cells were co-cultured with activated TECs. We analysed CD4(+) and CD8(+) T cell proliferation and apoptosis in the absence or presence of IDO inhibitor 1-methyl-L-tryptophan (1-L-MT), anti-PD-L1 and anti-ICAM-1. Further, we examined whether inhibition of T cell proliferation was cell-cell contact-dependent. We found that TECs dose-dependently inhibited CD4(+) and CD8(+) T cell proliferation (Pcell proliferation was only partially restored or failed to restore using 1-L-MT. Activated TECs increased early and late apoptosis of proliferating CD4(+) and CD8(+) T cells; only CD4(+) T cell apoptosis was statistically affected by 1-L-MT. Transwell experiments revealed that TEC-mediated immunosuppression is cell-cell contact-dependent. We found that anti-ICAM-1 affected only CD4(+) T cell apoptosis and not T cell proliferation. Our data show that TECs suppress both CD4(+) and CD8(+) T cell proliferation contact dependently. Interestingly, inhibition of proliferation and enhancement of apoptosis of T cell subsets is differentially regulated by indoleamine 2,3-dioxygenase and ICAM-1, with no evidence for the involvement of PD-L1 in our system. © 2014 British Society for Immunology.

  5. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts

    International Nuclear Information System (INIS)

    Cartellieri, M; Feldmann, A; Koristka, S; Arndt, C; Loff, S; Ehninger, A; Bonin, M von; Bejestani, E P; Ehninger, G; Bachmann, M P

    2016-01-01

    The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide ‘proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo

  6. Monoclonal antibody studies in B(non-T)-cell malignancies.

    Science.gov (United States)

    Shimoyama, M; Minato, K; Tobinai, K; Nagai, M; Hirose, M

    1983-09-01

    Tumor cells suspensions prepared from 129 B- or non-T cell malignancies were investigated with a panel of 10 monoclonal antibodies and conventional surface marker techniques. Surface immunoglobulin (sIg) and B1 antigen proved to be the most useful markers for B-cell lineage. Six major subtypes of acute lymphoblastic leukemia (ALL) of non-T cell nature are now recognized by these immunological techniques, including null-ALL, Ia-ALL, lymphoid stem cell ALL, pre-pre-B ALL, pre-B ALL and B-ALL. In cases of chronic leukemias and lymphomas of non-T cell nature, 80% of the tumor was defined by sIg and 88% by B1 antigen as definitely of B-cell lineage. The clonal character was also defined in 68% of the tumor on the basis of the detection of predominant single light chain in sIg. Ia-like antigen was detected in almost all cases (96%). Leukemic cells from all cases of chronic lymphocytic leukemia (CLL), chronic lymphosarcoma cell leukemia (CLsCL) and hairy cell leukemia (HCL) reacted with OKIa1 and anti-B1, and leukemic cells from most of them with anti-pan T monoclonal antibody (10.2). In more than half of CLL and CLsCL, leukemic cells were reactive with J5, OKM1, 9.6 and OKT8, but not with OKT3, OKT4 and OKT6. HCL cells had almost the same reactivity with these monoclonal antibodies as CLL and CLsCL cells except that J5 remained unreactive. These results indicated that Japanese CLL, CLsCL and HCL were different from Western ones at least with respect to surface marker characteristics. In cases of lymphomas, heavy chains of sIg were expressed in polyclonal fashion, especially in follicular lymphoma and diffuse lymphomas of medium sized cell type and large cell type, indicating that lymphomas of these types may originate from follicular center cells of the heavy chain switching stage. Anti-T monoclonals were also reactive with lymphoma cells. In about half of follicular lymphomas and diffuse lymphomas of the medium sized cell type, lymphoma cells reacted with 10.2, and less

  7. Impact of HIV on CD8+ T cell CD57 expression is distinct from that of CMV and aging.

    Directory of Open Access Journals (Sweden)

    Sulggi A Lee

    Full Text Available Chronic antigenic stimulation by cytomegalovirus (CMV is thought to increase "immunosenesence" of aging, characterized by accumulation of terminally differentiated CD28- CD8+ T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear.We compared markers of CD8+ T cell differentiation (e.g., CD28, CD27, CCR7, CD45RA and CD57 expression on CD28- CD8+ T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART-suppressed HIV-infected adults with asymptomatic CMV infection.Compared to HIV-uninfected adults without CMV (n=12, those with asymptomatic CMV infection (n=31 had a higher proportion of CD28-CD8+ T cells expressing CD57 (P=0.005. Older age was also associated with greater proportions of CD28-CD8+ T cells expressing CD57 (rho: 0.47, P=0.007. In contrast, untreated HIV-infected CMV+ participants (n=55 had much lower proportions of CD28- CD8+ cells expressing CD57 than HIV-uninfected CMV+ participants (P<0.0001 and were enriched for less well-differentiated CD28- transitional memory (TTR CD8+ T cells (P<0.0001. Chronically HIV-infected adults maintaining ART-mediated viral suppression (n=96 had higher proportions of CD28-CD8+ T cells expressing CD57 than untreated patients (P<0.0001, but continued to have significantly lower levels than HIV-uninfected controls (P=0.001. Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8+ T cells expressing CD57 declined (P<0.0001, which correlated with a decline in percent of transitional memory CD8+ T cells, and appeared to be largely explained by a decline in CD28-CD57- CD8+ T cell counts rather than an expansion of CD28-CD57+ CD8+ T cell counts.Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8+ T cells, HIV inhibits this process, expanding less well

  8. Clinicopathological study of anaplastic carcinoma of the thyroid gland

    International Nuclear Information System (INIS)

    Maeda, Akiteru; Umeno, Hirohito; Chijiwa, Hideki; Mihashi, Hiroyuki; Chitose, Shunichi; Nakashima, Tadashi

    2010-01-01

    Seventeen cases (5 males and 12 females) of anaplastic carcinoma of the thyroid gland treated at the Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, between January 1999 and January 2009 were reviewed. Ages of the patients ranged from 54 to 94 years. Six cases were treated by radical surgery. All cases were treated by radiotherapy and 5 cases received additional chemotherapy. The 6 cases treated by radical surgery were able to experience home life. Survival time of the radical surgery cases ranged from 8 to 36 months, with a median of 17 months. In cases without surgery, the survival time ranged from 1 to 8 months, with a median of 4 months. As the final outcome, only 1 case is alive after 36 months; 8 cases died by primary tumor, 7 by lung metastasis and 1 by suicide. Although the prognosis of anaplastic carcinoma of the thyroid gland is generally poor, radical surgery, if possible, may provide better survival results. (author)

  9. T-cell activation promotes tumorigenesis in inflammation-associated cancer

    Directory of Open Access Journals (Sweden)

    Lairmore Michael

    2009-12-01

    Full Text Available Abstract Chronic inflammation has long been associated with a wide range of malignancies, is now widely accepted as a risk factor for development of cancer, and has been implicated as a promoter of a variety of cancers including hematopoietic malignancies. We have described a mouse model uniquely suited to examine the link between inflammation and lymphoma in which the Tax oncogene, expressed in activated T and NK cells, perpetuates chronic inflammation that begins as microscopic intraepithelial lesions and develops into inflammatory nodules, subcutaneous tumors, and large granular lymphocytic leukemia. The use of bioluminescent imaging in these mice has expanded our ability to interrogate aspects of inflammation and tumorigenesis non-invasively. Here we demonstrate that bioluminescence induction in these mice correlated with inflammation resulting from wounding, T cell activation, and exposure to chemical agents. In experiments in which long-term effects of inflammation on disease outcome were monitored, the development of lymphoma was promoted by an inflammatory stimulus. Finally we demonstrated that activation of T-cells in T-cell receptor (TCR transgenic TAX-LUC animals dramatically exacerbated the development of subcutaneous TCR- CD16+ LGL tumors. The role of activated T-cells and acquired immunity in inflammation-associated cancers is broadly applicable to hematopoietic malignancies, and we propose these mice will be of use in dissecting mechanisms by which activated T-cells promote lymphomagenesis in vivo.

  10. IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis.

    Science.gov (United States)

    Luda, Katarzyna M; Joeris, Thorsten; Persson, Emma K; Rivollier, Aymeric; Demiri, Mimoza; Sitnik, Katarzyna M; Pool, Lieneke; Holm, Jacob B; Melo-Gonzalez, Felipe; Richter, Lisa; Lambrecht, Bart N; Kristiansen, Karsten; Travis, Mark A; Svensson-Frej, Marcus; Kotarsky, Knut; Agace, William W

    2016-04-19

    The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ(+) and CD4(+)CD8αα(+) T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103(+)CD11b(-) DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection.

    Directory of Open Access Journals (Sweden)

    Christophe Côme

    Full Text Available The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2AHOZ present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2AHOZ mice display an impaired adaptive immune response that is combined with decreased frequency of both CD4+ T-cells and CD8+ effector T-cells. Importantly, the cell autonomous effect of CIP2A deficiency for T-cell activation was confirmed. Induction of CIP2A expression during T-cell activation was dependent on Zap70 activity. Thus, we reveal CIP2A as a hitherto unrecognized mediator of T-cell activation during adaptive immune response. These results also reveal CIP2AHOZ as a possible novel mouse model for studying the role of PP2A activity in immune regulation. On the other hand, the results also indicate that CIP2A targeting cancer therapies would not cause serious immunological side-effects.

  12. CCL5 expression in panniculitic T-cell dyscrasias and its potential role in adipocyte tropism.

    Science.gov (United States)

    Magro, Cynthia M; Wang, Xuan

    2013-05-01

    Subcutaneous panniculitis-like T-cell lymphoma and gamma/delta T-cell lymphoma involving fat are unique among the hematologic dyscrasias because of their almost exclusive involvement of the subcutaneous fat with little tendency toward extracutaneous dissemination. The systemic manifestations associated with this lymphoma are largely the sequelae of cytokine production by neoplastic T cells found within the subcutaneous fat. We hypothesized that the basis of this localization could be due to an interactive microenvironment between the neoplastic cells and the adipocytes. Given the expression of CCR5 in adipocytes, we explored the expression of its ligand CCL5 in the subcutaneous infiltrates in subcutaneous panniculitis-like T-cell lymphoma, gamma/delta T-cell lymphoma and compared it with those in lupus erythematosus profundus (LEP). We found that CCL5 was expressed in a significantly higher percentage of lymphocytes in lymphomas compared with those in LEP (P tropism may reflect a unique interaction between CCL5-positive lymphocytes and CCR5 positive adipocytes. Given the known pharmacologic inhibitors of CCR5-expression one might propose that using such inhibitors (ie, anti-CCR5) could be of therapeutic value in select cases.

  13. CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy.

    Science.gov (United States)

    Li, Xiuhong; Margolick, Joseph B; Jamieson, Beth D; Rinaldo, Charles R; Phair, John P; Jacobson, Lisa P

    2011-08-15

    The heterogeneity of CD4 T-cell counts and HIV-1 RNA at 5-12 years after the initiation of highly active antiretroviral therapy (HAART) remains largely uncharacterized. In the Multicenter AIDS Cohort Study, 614 men who initiated HAART contributed data 5-12 years subsequently. Multivariate regression was used to evaluate the predictors of CD4 counts and HIV-1 RNA levels. At 5 to 12 years post-HAART, the median CD4 T-cell count was 586 (interquartile range, 421-791) cells per microliter and 78% of the HIV-1 RNA measurements were undetectable. Higher CD4 T-cell counts 5-12 years post HAART were predicted by higher CD4 T-cell counts and higher total lymphocyte count pre HAART, lack of hepatitis B or C virus coinfections, and greater CD4 T-cell change and suppressed HIV-1 RNA in the first 5 years after starting HAART. Men who were 50 years and older with 351-500 CD4 cells per microliter at HAART initiation had adjusted mean CD4 T-cell count of 643 cells per microliter at 10-12 years post HAART, which was similar to the adjusted mean CD4 T-cell count (670 cells/μL, P = 0.45) in this period for younger men starting HAART with lower CD4 T-cell counts. HIV-1 RNA suppression in the first 5 years post HAART predicted subsequent viral suppression. Immunological and virological responses in the first 5 years post HAART predicted subsequent CD4 T-cell counts and HIV-1 RNA levels. The association between age and subsequent CD4 T-cell count supports incorporating age in the guidelines for use of HAART.

  14. Elevated and cross-responsive CD1a-reactive T cells in bee and wasp venom allergic individuals.

    Science.gov (United States)

    Subramaniam, Sumithra; Aslam, Aamir; Misbah, Siraj A; Salio, Mariolina; Cerundolo, Vincenzo; Moody, D Branch; Ogg, Graham

    2016-01-01

    The role of CD1a-reactive T cells in human allergic disease is unknown. We have previously shown that circulating CD1a-reactive T cells recognize neolipid antigens generated by bee and wasp venom phospholipase, and here tested the hypothesis that venom-responsive CD1a-reactive T cells associate with venom allergy. Circulating T cells from bee and wasp venom allergic individuals, before and during immunotherapy, were exposed to CD1a-transfected K562 cells in the presence of wasp or bee venom. T-cell response was evaluated based on IFNγ, GM-CSF, and IL-13 cytokine production. Venom allergic individuals showed significantly higher frequencies of IFN-γ, GM-CSF, and IL-13 producing CD1a-reactive T cells responsive to venom and venom-derived phospholipase than healthy individuals. Venom-responsive CD1a-reactive T cells were cross-responsive between wasp and bee suggesting shared pathways of allergenicity. Frequencies of CD1a-reactive T cells were initially induced during subcutaneous immunotherapy, peaking by weeks 5, but then reduced despite escalation of antigen dose. Our current understanding of venom allergy and immunotherapy is largely based on peptide and protein-specific T cell and antibody responses. Here, we show that lipid antigens and CD1a-reactive T cells associate with the allergic response. These data have implications for mechanisms of allergy and approaches to immunotherapy. © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Abundance of early functional HIV-specific CD8+ T cells does not predict AIDS-free survival time.

    Directory of Open Access Journals (Sweden)

    Ingrid M M Schellens

    Full Text Available BACKGROUND: T-cell immunity is thought to play an important role in controlling HIV infection, and is a main target for HIV vaccine development. HIV-specific central memory CD8(+ and CD4(+ T cells producing IFNgamma and IL-2 have been associated with control of viremia and are therefore hypothesized to be truly protective and determine subsequent clinical outcome. However, the cause-effect relationship between HIV-specific cellular immunity and disease progression is unknown. We investigated in a large prospective cohort study involving 96 individuals of the Amsterdam Cohort Studies with a known date of seroconversion whether the presence of cytokine-producing HIV-specific CD8(+ T cells early in infection was associated with AIDS-free survival time. METHODS AND FINDINGS: The number and percentage of IFNgamma and IL-2 producing CD8(+ T cells was measured after in vitro stimulation with an overlapping Gag-peptide pool in T cells sampled approximately one year after seroconversion. Kaplan-Meier survival analysis and Cox proportional hazard models showed that frequencies of cytokine-producing Gag-specific CD8(+ T cells (IFNgamma, IL-2 or both shortly after seroconversion were neither associated with time to AIDS nor with the rate of CD4(+ T-cell decline. CONCLUSIONS: These data show that high numbers of functional HIV-specific CD8(+ T cells can be found early in HIV infection, irrespective of subsequent clinical outcome. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression.

  16. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma

    DEFF Research Database (Denmark)

    d'Amore, Francesco; Relander, Thomas; Lauritzsen, Grete F

    2012-01-01

    Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large...

  17. Glycolysis determines dichotomous regulation of T cell subsets in hypoxia

    Science.gov (United States)

    Xu, Yang; Zhang, Ming; Savoldo, Barbara; Metelitsa, Leonid S.; Rodgers, John; Yustein, Jason T.; Neilson, Joel R.

    2016-01-01

    Hypoxia occurs in many pathological conditions, including chronic inflammation and tumors, and is considered to be an inhibitor of T cell function. However, robust T cell responses occur at many hypoxic inflammatory sites, suggesting that functions of some subsets are stimulated under low oxygen conditions. Here, we investigated how hypoxic conditions influence human T cell functions and found that, in contrast to naive and central memory T cells (TN and TCM), hypoxia enhances the proliferation, viability, and cytotoxic action of effector memory T cells (TEM). Enhanced TEM expansion in hypoxia corresponded to high hypoxia-inducible factor 1α (HIF1α) expression and glycolytic activity compared with that observed in TN and TCM. We determined that the glycolytic enzyme GAPDH negatively regulates HIF1A expression by binding to adenylate-uridylate–rich elements in the 3′-UTR region of HIF1A mRNA in glycolytically inactive TN and TCM. Conversely, active glycolysis with decreased GAPDH availability in TEM resulted in elevated HIF1α expression. Furthermore, GAPDH overexpression reduced HIF1α expression and impaired proliferation and survival of T cells in hypoxia, indicating that high glycolytic metabolism drives increases in HIF1α to enhance TEM function during hypoxia. This work demonstrates that glycolytic metabolism regulates the translation of HIF1A to determine T cell responses to hypoxia and implicates GAPDH as a potential mechanism for controlling T cell function in peripheral tissue. PMID:27294526

  18. Cortisol patterns are associated with T cell activation in HIV.

    Directory of Open Access Journals (Sweden)

    Sarah Patterson

    Full Text Available The level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.We studied 128 HIV-infected adults who were not on treatment and had a CD4(+ T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.Lower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+ T cells (r = -0.26, p = 0.006. Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+ T cells (r = -0.17, p = 0.08. A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+ (r = 0.24, p = 0.018 and CD8(+ (r = 0.24, p = 0.017 activation.These data suggest that the hypothalamic-pituitary-adrenal (HPA axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV.

  19. Ulinastatin Reduces T Cell Apoptosis in Rats with Severe Acute ...

    African Journals Online (AJOL)

    T cell apoptosis was determined by Annexin-V/PI double-staining. Oxidative stress was evaluated by examining changes in the levels of reactive oxygen species (ROS). Total superoxide ... Key words: Ulinastatin, T cell, Apoptosis, Severe acute pancreatitis, Mitochondrion. Tropical ..... finally affect its structure and function.

  20. Using epigenetics to define vaccine-induced memory T cells.

    Science.gov (United States)

    Youngblood, Ben; Hale, J Scott; Akondy, Rama

    2013-06-01

    Memory T cells generated from acute infection or vaccination have the potential to provide the host with life-long immunity against re-infection. Protection by memory T cells is achieved through their acquired ability to persist at anatomical sites of the primary infection as well as maintaining a heightened ability to recall effector functions. The maintenance of CD8 and CD4 T cell function in a state of readiness is key to life-long immunity and manifest through changes in transcriptional regulation. Yet, the ability to identify poised transcriptional programs at the maintenance stage of the response is lacking from most transcriptional profiling studies of memory T cells. Epigenetic profiling allows for the assessment of transcriptionally poised (promoters that are readily accessible for transcription) states of antigen-specific T cells without manipulation of the activation state of the cell. Here we review recent studies that have examined epigenetic programs of effector and memory T cell subsets. These reports demonstrate that acquisition of epigenetic programs during memory T cell differentiation to acute and chronic infections is coupled to, and potentially regulate, the cell's recall response. We discuss the usefulness of epigenetic profiling in characterizing T cell differentiation state and function for preclinical evaluation of vaccines and the current methodologies for single locus versus genome-wide epigenetic profiling. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. T-cell mediated immunity in Wegener's granulomatosis

    NARCIS (Netherlands)

    Abdulahad, Wayel Habib

    2008-01-01

    Although the pathogenetic mechanisms involved in Wegener’s granulomatosis (WG) are not completely understood, considerable evidence support the concepts that activated T-cells play an important role in disease expression. It is, however, not clear which subsets of T-cells are involved in the

  2. T Cell Responses: Naive to Memory and Everything in Between

    Science.gov (United States)

    Pennock, Nathan D.; White, Jason T.; Cross, Eric W.; Cheney, Elizabeth E.; Tamburini, Beth A.; Kedl, Ross M.

    2013-01-01

    The authors describe the actions that take place in T cells because of their amazing capacity to proliferate and adopt functional roles aimed at clearing a host of an infectious agent. There is a drastic decline in the T cell population once the primary response is over and the infection is terminated. What remains afterward is a population of T…

  3. Genomewide analyses of pathogenic and regulatory T cells of NOD ...

    Indian Academy of Sciences (India)

    Reestablishing a well-balanced population of regulatory T cells (Tregs) and pathogenic T cells (Tpaths) is necessary for diabetic patients to regain glucose control. However, the molecular mechanisms modulating functional differentiation of Tpaths and Tregs remain unclear. In this study, we anal- ysed the gene expression ...

  4. Auto-reactive T cells revised. Overestimation based on methodology?

    DEFF Research Database (Denmark)

    Thorlacius-Ussing, Gorm; Sørensen, Jesper F; Wandall, Hans H

    2015-01-01

    Autoreactive T cells have been identified in most autoimmune diseases and recently even in healthy individuals. Similar, T cells that recognize either wild-type or tumorspecific tumor antigens have been increasingly reported to develop spontaneously in cancer patients. This insight has become pos...

  5. Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Fernanda O Novais

    Full Text Available Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8⁺ T cells following infection with the intracellular parasite Leishmania, CD8⁺ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8⁺ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8⁺ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8⁺ T cells. In mice with severe pathology, we visualized CD8⁺ T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8⁺ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8⁺ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.

  6. Prospects and limitations of T cell receptor gene therapy

    NARCIS (Netherlands)

    Jorritsma, Annelies; Schotte, Remko; Coccoris, Miriam; de Witte, Moniek A.; Schumacher, Ton N. M.

    2011-01-01

    Adoptive transfer of antigen-specific T cells is an attractive means to provide cancer patients with immune cells of a desired specificity and the efficacy of such adoptive transfers has been demonstrated in several clinical trials. Because the T cell receptor is the single specificity-determining

  7. Parathyroid hormone dependent T cell proliferation in uremic rats

    DEFF Research Database (Denmark)

    Lewin, E; Ladefoged, Jens; Brandi, L

    1993-01-01

    Chronic renal failure (CRF) is combined with an impairment of the immune system. The T cell may be a target for the action of parathyroid hormone (PTH). Rats with CRF have high blood levels of PTH. Therefore, the present investigation examined some aspects of the T cell function in both normal...

  8. Structural elements recognized by abacavir-induced T cells

    DEFF Research Database (Denmark)

    Yerly, Daniel; Pompeu, Yuri Andreiw; Schutte, Ryan J.

    2017-01-01

    of autoimmune destruction. The structural elements recognized by drug-specific T cell receptors (TCRs) in vivo are poorly defined. Drug-stimulated T cells express TCRs specific for peptide/HLA complexes, but the characteristics of peptides (sequence, or endogenous or exogenous origin) presented in the context...

  9. How do i participate in T-cell immunotherapy?

    Science.gov (United States)

    Suhoski Davis, Megan M; McKenna, David H; Norris, Philip J

    2017-05-01

    T cells play a key role in the adaptive immune response, and the ability to manipulate T cells for therapeutic uses has advanced in the past decade. Infusion of expanded or engineered T cells can potentially be used to treat cancer, viral infections, graft-versus-host disease, and organ transplant rejection. The role that blood banks play in the manufacture and distribution of T-cell therapeutics is still being defined. Given the regulatory framework of blood banks, they are well positioned to collect raw material for manufacture of T-cell therapies and to distribute finished product to hospitals in support of clinical trials or eventually for licensed products. A deeper level of involvement in manufacture of T-cell therapeutics is also possible, although that requires more substantial investment in physical facilities and personnel with the regulatory and scientific expertise to prepare and produce cellular therapy products. Examples of physical infrastructure needed would be a laboratory with a clean room for culture of T cells, specialized equipment for expansion of the cells, and adequate administrative and storage support space. Processes that would need to be developed to produce T-cell therapeutics would include development of standard operating procedures and an appropriate quality assurance program. As blood banks consider supporting this novel class of therapies, they will need to weigh capital and expertise requirements with the benefits of providing a novel therapy and the potential of growth for their operations. © 2017 AABB.

  10. High epitope expression levels increase competition between T cells.

    Directory of Open Access Journals (Sweden)

    Almut Scherer

    2006-08-01

    Full Text Available Both theoretical predictions and experimental findings suggest that T cell populations can compete with each other. There is some debate on whether T cells compete for aspecific stimuli, such as access to the surface on antigen-presenting cells (APCs or for specific stimuli, such as their cognate epitope ligand. We have developed an individual-based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell competition is mainly for specific or aspecific stimuli. Under low epitope expression, competition is mainly for the specific epitope stimuli, and, hence, different epitope-specific T cell populations coexist readily. However, if epitope expression levels are high, aspecific competition becomes more important. Such between-specificity competition can lead to competitive exclusion between different epitope-specific T cell populations. Our model allows us to delineate the circumstances that facilitate coexistence of T cells of different epitope specificity. Understanding mechanisms of T cell coexistence has important practical implications for immune therapies that require a broad immune response.

  11. T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire.

    Science.gov (United States)

    Beausang, John F; Wheeler, Amanda J; Chan, Natalie H; Hanft, Violet R; Dirbas, Frederick M; Jeffrey, Stefanie S; Quake, Stephen R

    2017-11-28

    Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment. Copyright © 2017 the Author(s). Published by PNAS.

  12. Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria in the mouse.

    Directory of Open Access Journals (Sweden)

    Marc Bajénoff

    Full Text Available Memory CD8(+ T cells represent an important effector arm of the immune response in maintaining long-lived protective immunity against viruses and some intracellular bacteria such as Listeria monocytogenes (L.m. Memory CD8(+ T cells are endowed with enhanced antimicrobial effector functions that perfectly tail them to rapidly eradicate invading pathogens. It is largely accepted that these functions are sufficient to explain how memory CD8(+ T cells can mediate rapid protection. However, it is important to point out that such improved functional features would be useless if memory cells were unable to rapidly find the pathogen loaded/infected cells within the infected organ. Growing evidences suggest that the anatomy of secondary lymphoid organs (SLOs fosters the cellular interactions required to initiate naive adaptive immune responses. However, very little is known on how the SLOs structures regulate memory immune responses. Using Listeria monocytogenes (L.m as a murine infection model and imaging techniques, we have investigated if and how the architecture of the spleen plays a role in the reactivation of memory CD8(+ T cells and the subsequent control of L.m growth. We observed that in the mouse, memory CD8(+ T cells start to control L.m burden 6 hours after the challenge infection. At this very early time point, L.m-specific and non-specific memory CD8(+ T cells localize in the splenic red pulp and form clusters around L.m infected cells while naïve CD8(+ T cells remain in the white pulp. Within these clusters that only last few hours, memory CD8(+ T produce inflammatory cytokines such as IFN-gamma and CCL3 nearby infected myeloid cells known to be crucial for L.m killing. Altogether, we describe how memory CD8(+ T cells trafficking properties and the splenic micro-anatomy conjugate to create a spatio-temporal window during which memory CD8(+ T cells provide a local response by secreting effector molecules around infected cells.

  13. Asymmetric cell division during T cell development controls downstream fate

    Science.gov (United States)

    Pham, Kim; Shimoni, Raz; Charnley, Mirren; Ludford-Menting, Mandy J.; Hawkins, Edwin D.; Ramsbottom, Kelly; Oliaro, Jane; Izon, David; Ting, Stephen B.; Reynolds, Joseph; Lythe, Grant; Molina-Paris, Carmen; Melichar, Heather; Robey, Ellen; Humbert, Patrick O.; Gu, Min

    2015-01-01

    During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal. PMID:26370500

  14. Hidden memories: frontline memory T cells and early pathogen interception.

    Science.gov (United States)

    Masopust, David; Picker, Louis J

    2012-06-15

    Immunologic memory reflects the ability of a host to more effectively respond to a re-encounter with a particular pathogen than the first encounter, and when a vaccine mimics the first encounter, comprises the basis of vaccine efficacy. For T cells, memory is often equated with the anamnestic response, the ability of secondary lymphoid tissue-based (central) memory T cells to respond to pathogen exposure with a more rapid and higher magnitude production and infection-site delivery of pathogen-specific effector cells than observed in naive hosts. However, increasing evidence supports a fundamentally different kind of T cell memory in which differentiated, long-lived effector memory T cells, prepositioned in sites of potential pathogen invasion or rapidly mobilized to such sites from blood and marginated pools, intercept and potentially control/eliminate pathogen within hours of infection. In this article, we review the evidence for this "hidden" T cell memory and its implication for vaccine development.

  15. Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials.

    Science.gov (United States)

    Esensten, Jonathan H; Bluestone, Jeffrey A; Lim, Wendell A

    2017-01-24

    Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field.

  16. Ets transcription factor GABP controls T cell homeostasis and immunity.

    Science.gov (United States)

    Luo, Chong T; Osmanbeyoglu, Hatice U; Do, Mytrang H; Bivona, Michael R; Toure, Ahmed; Kang, Davina; Xie, Yuchen; Leslie, Christina S; Li, Ming O

    2017-10-20

    Peripheral T cells are maintained in the absence of vigorous stimuli, and respond to antigenic stimulation by initiating cell cycle progression and functional differentiation. Here we show that depletion of the Ets family transcription factor GA-binding protein (GABP) in T cells impairs T-cell homeostasis. In addition, GABP is critically required for antigen-stimulated T-cell responses in vitro and in vivo. Transcriptome and genome-wide GABP-binding site analyses identify GABP direct targets encoding proteins involved in cellular redox balance and DNA replication, including the Mcm replicative helicases. These findings show that GABP has a nonredundant role in the control of T-cell homeostasis and immunity.

  17. Induction of IL-10- and IFN-gamma-producing T-cell responses by autoreactive T-cells expressing human T-cell leukemia virus type I Tax.

    Science.gov (United States)

    Takatsuka, Natsuko; Hasegawa, Atsuhiko; Takamori, Ayako; Shimizu, Yukiko; Kato, Hirotomo; Ohashi, Takashi; Amagasa, Teruo; Masuda, Takao; Kannagi, Mari

    2009-09-01

    Human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell leukemia, HTLV-I-associated myelopathy/tropical spastic paraparesis and various autoimmune-like disorders. T-cell immune suppression is also associated with HTLV-I infection. Mechanisms of diverse immune dysregulation in HTLV-I infection are obscure. Here, we investigated a potential link between autoimmunity and immune suppression in HTLV-I infection. G14, an IL-2-dependent HTLV-I-negative CD4(+)CD8(+) T-cell line previously established from an HTLV-I-infected rat, constantly proliferated and produced IFN-gamma. IFN-gamma production by G14 cells was dependent on interactions between CD4 and MHC-II, suggesting that G14 cells recognized self-antigens presented by MHC-II on themselves. To examine immune response to G14 cells, we inoculated G14 cells into syngeneic naive rats. Interestingly, T-cells isolated from these rats vigorously proliferated when stimulated with G14-Tax cells that stably expressed HTLV-I Tax, but not with G14 cells. G14-Tax-mediated T-cell proliferation was abrogated by antibodies to CD80 and CD86 that were up-regulated in G14-Tax cells. T-cells propagated by repetitive G14-Tax cell stimulations in culture with IL-2 expressed CD4, CD25 and cytolytic T lymphocyte-associated antigen 4 (CTLA-4), produced abundant amounts of IL-10 and IFN-gamma in response to G14 cells and suppressed growth of G14 cells mainly through supernatant-mediated mechanisms. Similar IL-10- and IFN-gamma-producing CD4(+)CD25(+)CTLA-4(+) T-cells were predominantly induced in culture of splenocytes from HTLV-I-infected rats following stimulation with G14-Tax cells. These results implied that expression of Tax in the otherwise low immunogenic autoreactive T-cells induced IL-10- and IFN-gamma-producing T-cell responses with regulatory effects against the autoreactive cells. Our findings provide new insights into the complex immune conditions underlying HTLV-I-associated diseases.

  18. Role of the mononuclear phagocyte as an antigen-presenting cell for human gamma delta T cells activated by live Mycobacterium tuberculosis.

    OpenAIRE

    Boom, W H; Chervenak, K A; Mincek, M A; Ellner, J J

    1992-01-01

    gamma delta T cells, both human and murine, have been found to be highly responsive to mycobacterial antigens. However, the role and function of gamma delta T cells in the immune response to Mycobacterium tuberculosis remain largely unknown. In earlier studies, we demonstrated that monocytes infected with live M. tuberculosis were particularly effective inducers of human peripheral blood gamma delta T cells. The present studies were performed to further characterize the interaction between hu...

  19. Clinical applications of gamma delta T cells with multivalent immunity

    Directory of Open Access Journals (Sweden)

    Drew C Deniger

    2014-12-01

    Full Text Available Gamma delta T cells hold promise for adoptive immunotherapy because of their reactivity to bacteria, viruses, and tumors. However, these cells represent a small fraction (1-5% of the peripheral T-cell pool and require activation and propagation to achieve clinical benefit. Aminobisphosphonates specifically expand the Vgamma9Vdelta2 subset of gamma delta T cells and have been used in clinical trials of cancer where objective responses were detected. The Vgamma9Vdelta2 TCR heterodimer binds multiple ligands and results in a multivalent attack by a monoclonal T cell population. Alternatively, populations of gamma delta T cells with oligoclonal or polyclonal TCR repertoire could be infused for broad-range specificity. However, this goal has been restricted by a lack of applicable expansion protocols for non-Vgamma9Vdelta2 cells. Recent advances using immobilized antigens, agonistic monoclonal antibodies (mAbs, tumor-derived artificial antigen presenting cells (aAPC, or combinations of activating mAbs and aAPC have been successful in expanding gamma delta T cells with oligoclonal or polyclonal TCR repertoires. Immobilized MHC Class-I chain-related A was a stimulus for gamma delta T cells expressing TCRdelta1 isotypes, and plate-bound activating antibodies have expanded Vdelta1 and Vdelta2 cells ex vivo. Clinically-sufficient quantities of TCRdelta1, TCRdelta2, and TCRdelta1negTCRdelta2neg have been produced following co-culture on aAPC, and these subsets displayed differences in memory phenotype and reactivity to tumors in vitro and in vivo. Gamma delta T cells are also amenable to genetic modification as evidenced by introduction of alpha beta TCRs, chimeric antigen receptors (CARs, and drug-resistance genes. This represents a promising future for the clinical application of oligoclonal or polyclonal gamma delta T cells in autologous and allogeneic settings that builds on current trials testing the safety and efficacy of Vgamma9Vdelta2 T cells.

  20. Significant Depletion of CD4+ T Cells Occurs in the Oral Mucosa during Simian Immunodeficiency Virus Infection with the Infected CD4+ T Cell Reservoir Continuing to Persist in the Oral Mucosa during Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Jeffy George

    2015-01-01

    Full Text Available Human and simian immunodeficiency virus (HIV and SIV infections are characterized by manifestation of numerous opportunistic infections and inflammatory conditions in the oral mucosa. The loss of CD4+ T cells that play a critical role in maintaining mucosal immunity likely contributes to this process. Here we show that CD4+ T cells constitute a minor population of T cells in the oral mucosa and display a predominantly central memory phenotype mirroring other mucosal sites such as the rectal mucosa. Chronic SIV infection was associated with a near total depletion of CD4+ T cells in the oral mucosa that appear to repopulate during antiretroviral therapy (ART. Repopulating CD4+ T cells harbored a large fraction of Th17 cells suggesting that ART potentially reconstitutes oral mucosal immunity. However, a minor fraction of repopulating CD4+ T cells harbored SIV DNA suggesting that the viral reservoir continues to persist in the oral mucosa during ART. Therapeutic approaches aimed at obtaining sustainable CD4+ T cell repopulation in combination with strategies that can eradicate the latent viral reservoir in the oral mucosa are essential for better oral health and long-term outcome in HIV infected patients.

  1. Utilization of two different T cell receptors by T cell acute lymphoblastic lymphoma and leukemia.

    Science.gov (United States)

    Gouttefangeas, C; Bensussan, A; Boumsell, L

    1990-01-01

    We show further differences between two clinically related entities, T cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), by using several monoclonal antibodies (mAb) reacting either with constant or variable regions of T cell receptors (TcR) alpha beta and gamma delta or with various CD molecules. We analysed a panel of 15 T-ALL and 15 T-LL selected for their cell surface expression of the CD3 molecules. The results indicate that TcR gamma delta is more frequently used than TcR alpha beta in T-ALL (10 out of the 15 patients tested). This is in contrast to the results obtained with T-LL where the vast majority expressed TcR alpha beta (13 out of the 15 patients). These findings suggest that the leukemic cells could have a different origin in these two diseases. In addition analysis of TcR variable regions expressed by the leukemic blasts showed that in most cases they had rearranged functional V delta 1 gene segments (8 out of 11 patients) whereas in a unique case V delta 2 gene segment was used. Taken together these results and those indicating that T-ALL cell coexpress the CD1a,b and c molecules strengthen the possibility that even though these leukemic cells express the CD3-TcR complex at their cell surface their normal counterparts are not found in peripheral blood.

  2. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

    Directory of Open Access Journals (Sweden)

    Verhoef Adrienne

    2005-01-01

    Full Text Available Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

  3. GM-CSF Production Allows the Identification of Immunoprevalent Antigens Recognized by Human CD4+ T Cells Following Smallpox Vaccination

    Science.gov (United States)

    Judkowski, Valeria; Bunying, Alcinette; Ge, Feng; Appel, Jon R.; Law, Kingyee; Sharma, Atima; Raja- Gabaglia, Claudia; Norori, Patricia; Santos, Radleigh G.; Giulianotti, Marc A.; Slifka, Mark K.; Douek, Daniel C.; Graham, Barney S.; Pinilla, Clemencia

    2011-01-01

    The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a “T cell–driven” methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens. PMID:21931646

  4. Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas

    DEFF Research Database (Denmark)

    Marquard, L.; Poulsen, C.B.; Gjerdrum, L.M.

    2009-01-01

    AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim was to det......AIMS: Histone deacetylase (HDAC) inhibitors are novel therapeutics in the treatment of peripheral T-cell lymphoma, unspecified (PTCL) and diffuse large B-cell lymphoma (DLBCL), where, for unknown reasons, T-cell malignancies appear to be more sensitive than B-cell malignancies. The aim...... was to determine HDAC expression in DLBCL and PTCL which has not previously been investigated. METHODS AND RESULTS: The expression of HDAC1, HDAC2, HDAC6 and acetylated histone H4 was examined immunohistochemically in 31 DLBCL and 45 PTCL. All four markers showed high expression in both DLBCL and PTCL compared...

  5. NOD1 cooperates with TLR2 to enhance T cell receptor-mediated activation in CD8 T cells.

    Directory of Open Access Journals (Sweden)

    Blandine C Mercier

    Full Text Available Pattern recognition receptors (PRR, like Toll-like receptors (TLR and NOD-like receptors (NLR, are involved in the detection of microbial infections and tissue damage by cells of the innate immune system. Recently, we and others have demonstrated that TLR2 can additionally function as a costimulatory receptor on CD8 T cells. Here, we establish that the intracytosolic receptor NOD1 is expressed and functional in CD8 T cells. We show that C12-iEDAP, a synthetic ligand for NOD1, has a direct impact on both murine and human CD8 T cells, increasing proliferation and effector functions of cells activated via their T cell receptor (TCR. This effect is dependent on the adaptor molecule RIP2 and is associated with an increased activation of the NF-κB, JNK and p38 signaling pathways. Furthermore, we demonstrate that NOD1 stimulation can cooperate with TLR2 engagement on CD8 T cells to enhance TCR-mediated activation. Altogether our results indicate that NOD1 might function as an alternative costimulatory receptor in CD8 T cells. Our study provides new insights into the function of NLR in T cells and extends to NOD1 the recent concept that PRR stimulation can directly control T cell functions.

  6. Antigen-specific T cell activation independently of the MHC: chimeric antigen receptor (CAR-redirected T cells.

    Directory of Open Access Journals (Sweden)

    Hinrich eAbken

    2013-11-01

    Full Text Available Adoptive T cell therapy has recently shown powerful in initiating a lasting anti-tumor response with spectacular therapeutic success in some cases. Specific T cell therapy, however, is limited since a number of cancer cells are not recognized by T cells due to various mechanisms including the limited availability of tumor-specific T cells and deficiencies in antigen processing or major histocompatibility complex (MHC expression of cancer cells. To make adoptive cell therapy applicable for the broad variety of cancer entities, patient's T cells are engineered ex vivo with pre-defined specificity by a recombinant chimeric antigen receptor (CAR which consists in the extracellular part of an antibody-derived domain for binding with a tumor-associated antigen and in the intracellular part of a TCR-derived signaling moiety for T cell activation. The specificity of CAR mediated T cell recognition is defined by the antibody domain, is independent of MHC presentation and can be extended to any target for which an antibody is available. We discuss the advantages and limitations of MHC-independent T cell targeting by an engineered CAR and review most significant progress recently made in early stage clinical trials to treat cancer.

  7. T cell maturation stage prior to and during GMP processing informs on CAR T cell expansion in patients

    NARCIS (Netherlands)

    Y. Klaver (Yarne); S.C.L. van Steenbergen; S. Sleijfer (Stefan); J.E.M.A. Debets (Reno); C.H.J. Lamers (Cor)

    2016-01-01

    textabstractAutologous T cells were genetically modified to express a chimeric antigen receptor (CAR) directed toward carboxy-anhydrase-IX (CAIX) and used to treat patients with CAIX-positive metastatic renal cell carcinoma. In this study, we questioned whether the T cell maturation stage in the

  8. Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion

    DEFF Research Database (Denmark)

    Brimnes, Marie Klinge; Gang, Anne Ortved; Donia, Marco

    2012-01-01

    , for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads® CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells...... that were both cytotoxic and effective cytokine producers upon antigen recognition. Dynabeads®-expanded T-cell cultures shows phenotypical characteristics of memory T cells with potential to migrate and expand in vivo. In addition, they possess longer telomeres compared to TIL cultures. Taken together, we...

  9. Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance

    Science.gov (United States)

    Ma, Liang; Mauro, Claudio; Cornish, Georgina H.; Chai, Jian-Guo; Coe, David; Fu, Hongmei; Patton, Daniel; Okkenhaug, Klaus; Franzoso, Guido; Dyson, Julian; Nourshargh, Sussan; Marelli-Berg, Federica M.

    2010-01-01

    CD31 is an Ig-like molecule expressed by leukocytes and endothelial cells with an established role in the regulation of leukocyte trafficking. Despite genetic deletion of CD31 being associated with exacerbation of T cell-mediated autoimmunity, the contribution of this molecule to T-cell responses is largely unknown. Here we report that tumor and allograft rejection are significantly enhanced in CD31-deficient mice, which are also resistant to tolerance induction. We propose that these effects are dependent on an as yet unrecognized role for CD31-mediated homophilic interactions between T cells and antigen-presenting cells (APCs) during priming. We show that loss of CD31 interactions leads to enhanced primary clonal expansion, increased killing capacity, and diminished regulatory functions by T cells. Immunomodulation by CD31 signals correlates with a partial inhibition of proximal T-cell receptor (TCR) signaling, specifically Zap-70 phosphorylation. However, CD31-deficient mice do not develop autoimmunity due to increased T-cell death following activation, and we show that CD31 triggering induces Erk-mediated prosurvival activity in T cells either in conjunction with TCR signaling or autonomously. We conclude that CD31 functions as a nonredundant comodulator of T-cell responses, which specializes in sizing the ensuing immune response by setting the threshold for T-cell activation and tolerance, while preventing memory T-cell death. PMID:20978210

  10. CD4+CD8β+ double-positive T cells in skin-draining lymph nodes respond to inflammatory signals from the skin

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr; Cruz, Jazmina L.; Bridge, Jennifer A.

    2017-01-01

    CD4+CD8+ double-positive (DP), mature, peripheral T cells are readily detectable in a variety of species and tissues. Despite a common association with autoimmune and malignant skin disorders, however, little is understood about their role or function. Herein, we show that DP T cells are readily...... detectable in the blood, spleen, and peripheral lymph nodes of naïve C57BL/6 mice. DP T cells were also present in Jα-/- and CD1d-/- mice, indicating that these cells are not NK-T cells. After skin administration of CASAC adjuvant, but not Quil A adjuvant, both total DP T cells and skin-infiltrating DP T...... cells increased in number. We explored the possibility that DP T cells could represent aggregates between CD4+ and CD8+ single-positive T cells and found strong evidence that a large proportion of apparent DP T cells were indeed aggregates. However, the existence of true CD4+CD8+ DP T cells...

  11. Origin of Enriched Regulatory T Cells in Patients Receiving Combined Kidney-Bone Marrow Transplantation to Induce Transplantation Tolerance.

    Science.gov (United States)

    Sprangers, B; DeWolf, S; Savage, T M; Morokata, T; Obradovic, A; LoCascio, S A; Shonts, B; Zuber, J; Lau, S P; Shah, R; Morris, H; Steshenko, V; Zorn, E; Preffer, F I; Olek, S; Dombkowski, D M; Turka, L A; Colvin, R; Winchester, R; Kawai, T; Sykes, M

    2017-08-01

    We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney-bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-β hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3 + CD4 + CD25 high CD127 low Foxp3 + ) in blood that resulted from peripheral proliferation (Ki67 + ), possibly new thymic emigration (CD31 + ), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4 + and CD8 + cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  12. Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution.

    Science.gov (United States)

    Luther, Natascha; Shahneh, Fatemeh; Brähler, Melanie; Krebs, Franziska; Jäckel, Sven; Subramaniam, Saravanan; Stanger, Christian; Schönfelder, Tanja; Kleis-Fischer, Bettina; Reinhardt, Christoph; Probst, Hans Christian; Wenzel, Philip; Schäfer, Katrin; Becker, Christian

    2016-12-09

    Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in sterile inflammation in venous thrombosis has not been systematically examined. This study investigated the recruitment, activation, and inflammatory activity of T cells in deep vein thrombosis and its consequences for venous thrombus resolution. CD4 + and CD8 + T cells infiltrate the thrombus and vein wall rapidly on deep vein thrombosis induction and remain in the tissue throughout the thrombus resolution. In the vein wall, recruited T cells largely consist of effector-memory T (T EM ) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited T EM receive an immediate antigen-independent activation and produce IFN-γ (interferon) in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of deep vein thrombosis upregulated cytokines and chemokines that synergize to induce antigen-independent IFN-γ production in CD4 + and CD8 + T EM cells. Reducing the number of T EM cells through a depletion recovery procedure, we show that intravenous T EM activation determines neutrophil and monocyte recruitment and delays thrombus neovascularization and resolution. Examining T-cell recruitment in human venous stasis, we show that superficial varicose veins preferentially contain activated memory T cells. T EM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution. © 2016 American Heart Association, Inc.

  13. γδ T Cell-Dependent Regulatory T Cells Prevent the Development of Autoimmune Keratitis1

    Science.gov (United States)

    Huang, Yafei; Yang, Zhifang; Huang, Chunjian; McGowan, Jessica; Casper, Tamara; Sun, Deming; Born, Willi K.; O’Brien, Rebecca L.

    2015-01-01

    To prevent potentially damaging inflammatory responses, the eye actively promotes local immune tolerance via a variety of mechanisms. Due to trauma, infection, or other ongoing autoimmunity, these mechanisms sometimes fail, and an autoimmune disorder may develop in the eye. In mice of the C57BL/10 (B10) background, autoimmune keratitis often develops spontaneously, particularly in the females. Its incidence is greatly elevated in the absence of γδ T cells, such that about 80% of female B10.TCRδ−/− mice develop keratitis by 18 weeks of age. Here, we show that CD8+ αβ T cells are the drivers of this disease, because adoptive transfer of CD8+ but not CD4+ T cells to keratitis-resistant B10.TCRβ/δ−/− hosts induced a high incidence of keratitis. This was unexpected because in other autoimmune diseases, more often CD4+ αβ T cells, or both CD4+ and CD8+ αβ T cells, mediate the disease. Compared to wildtype B10 mice, B10.TCRδ−/− mice also show increased percentages of peripheral memory phenotype CD8+ αβ T cells, along with an elevated frequency of CD8+ αβ T cells biased to produce inflammatory cytokines. B10.TCRδ−/− mice in addition have fewer peripheral CD4+ CD25+ FoxP3+ regulatory αβ T cells (Tregs), which express lower levels of receptors needed for Treg development and function. Together, these observations suggest that in B10 background mice, γδ T cells are required to generate adequate numbers of CD4+ CD25+ FoxP3+ Tregs, and that in B10.TCRδ−/− mice a Treg deficiency allows dysregulated effector or memory CD8+ αβ T cells to infiltrate the cornea and provoke an autoimmune attack. PMID:26566677

  14. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies.

    Science.gov (United States)

    Png, Yi Tian; Vinanica, Natasha; Kamiya, Takahiro; Shimasaki, Noriko; Coustan-Smith, Elaine; Campana, Dario

    2017-11-28

    Effective immunotherapies for T-cell malignancies are lacking. We devised a novel approach based on chimeric antigen receptor (CAR)-redirected T lymphocytes. We selected CD7 as a target because of its consistent expression in T-cell acute lymphoblastic leukemia (T-ALL), including the most aggressive subtype, early T-cell precursor (ETP)-ALL. In 49 diagnostic T-ALL samples (including 14 ETP-ALL samples), median CD7 expression was >99%; CD7 expression remained high at relapse (n = 14), and during chemotherapy (n = 54). We targeted CD7 with a second-generation CAR (anti-CD7-41BB-CD3ζ), but CAR expression in T lymphocytes caused fratricide due to the presence of CD7 in the T cells themselves. To downregulate CD7 and control fratricide, we applied a new method (protein expression blocker [PEBL]), based on an anti-CD7 single-chain variable fragment coupled with an intracellular retention domain. Transduction of anti-CD7 PEBL resulted in virtually instantaneous abrogation of surface CD7 expression in all transduced T cells; 2.0% ± 1.7% were CD7 + vs 98.1% ± 1.5% of mock-transduced T cells (n = 5; P < .0001). PEBL expression did not impair T-cell proliferation, interferon-γ and tumor necrosis factor-α secretion, or cytotoxicity, and eliminated CAR-mediated fratricide. PEBL-CAR T cells were highly cytotoxic against CD7 + leukemic cells in vitro and were consistently more potent than CD7 + T cells spared by fratricide. They also showed strong anti-leukemic activity in cell line- and patient-derived T-ALL xenografts. The strategy described in this study fits well with existing clinical-grade cell manufacturing processes and can be rapidly implemented for the treatment of patients with high-risk T-cell malignancies.

  15. Enhancement of T cell responses as a result of synergy between lower doses of radiation and T cell stimulation.

    Science.gov (United States)

    Spary, Lisa K; Al-Taei, Saly; Salimu, Josephine; Cook, Alexander D; Ager, Ann; Watson, H Angharad; Clayton, Aled; Staffurth, John; Mason, Malcolm D; Tabi, Zsuzsanna

    2014-04-01

    As a side effect of cancer radiotherapy, immune cells receive varying doses of radiation. Whereas high doses of radiation (>10 Gy) can lead to lymphopenia, lower radiation doses (2-4 Gy) represent a valid treatment option in some hematological cancers, triggering clinically relevant immunological changes. Based on our earlier observations, we hypothesized that lower radiation doses have a direct positive effect on T cells. In this study, we show that 0.6-2.4 Gy radiation enhances proliferation and IFN-γ production of PBMC or purified T cells induced by stimulation via the TCR. Radiation with 1.2 Gy also lowered T cell activation threshold and broadened the Th1 cytokine profile. Although radiation alone did not activate T cells, when followed by TCR stimulation, ERK1/2 and Akt phosphorylation increased above that induced by stimulation alone. These changes were followed by an early increase in glucose uptake. Naive (CD45RA(+)) or memory (CD45RA(-)) T cell responses to stimulation were boosted at similar rates by radiation. Whereas increased Ag-specific cytotoxic activity of a CD8(+) T cell line manifested in a 4-h assay (10-20% increase), highly significant (5- to 10-fold) differences in cytokine production were detected in 6-d Ag-stimulation assays of PBMC, probably as a net outcome of death of nonstimulated and enhanced response of Ag-stimulated T cells. T cells from patients receiving pelvic radiation (2.2-2.75 Gy) also displayed increased cytokine production when stimulated in vitro. We report in this study enhanced T cell function induced by synergistic radiation treatment, with potential physiological significance in a wide range of T cell responses.

  16. HIV-1 transgenic rats develop T cell abnormalities

    International Nuclear Information System (INIS)

    Reid, William; Abdelwahab, Sayed; Sadowska, Mariola; Huso, David; Neal, Ashley; Ahearn, Aaron; Bryant, Joseph; Gallo, Robert C.; Lewis, George K.; Reitz, Marvin

    2004-01-01

    HIV-1 infection leads to impaired antigen-specific T cell proliferation, increased susceptibility of T cells to apoptosis, progressive impairment of T-helper 1 (Th1) responses, and altered maturation of HIV-1-specific memory cells. We have identified similar impairments in HIV-1 transgenic (Tg) rats. Tg rats developed an absolute reduction in CD4 + and CD8 + T cells able to produce IFN-γ following activation and an increased susceptibility of T cells to activation-induced apoptosis. CD4 + and CD8 + effector/memory (CD45RC - CD62L - ) pools were significantly smaller in Tg rats compared to non-Tg controls, although the converse was true for the naieve (CD45RC + CD62L + ) T cell pool. Our interpretation is that the HIV transgene causes defects in the development of T cell effector function and generation of specific effector/memory T cell subsets, and that activation-induced apoptosis may be an essential factor in this process

  17. Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma.

    Science.gov (United States)

    Orlando, Domenico; Miele, Evelina; De Angelis, Biagio; Guercio, Marika; Boffa, Iolanda; Sinibaldi, Matilde; Po, Agnese; Caruana, Ignazio; Abballe, Luana; Carai, Andrea; Caruso, Simona; Camera, Antonio; Moseley, Annemarie; Hagedoorn, Renate S; Heemskerk, Mirjam H M; Giangaspero, Felice; Mastronuzzi, Angela; Ferretti, Elisabetta; Locatelli, Franco; Quintarelli, Concetta

    2018-04-03

    Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T cell-related toxicity,an inducible caspase 9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically-modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients. Copyright ©2018, American Association for Cancer Research.

  18. The role of CD8+ T cells during allograft rejection

    Directory of Open Access Journals (Sweden)

    V. Bueno

    2002-11-01

    Full Text Available Organ transplantation can be considered as replacement therapy for patients with end-stage organ failure. The percent of one-year allograft survival has increased due, among other factors, to a better understanding of the rejection process and new immunosuppressive drugs. Immunosuppressive therapy used in transplantation prevents activation and proliferation of alloreactive T lymphocytes, although not fully preventing chronic rejection. Recognition by recipient T cells of alloantigens expressed by donor tissues initiates immune destruction of allogeneic transplants. However, there is controversy concerning the relative contribution of CD4+ and CD8+ T cells to allograft rejection. Some animal models indicate that there is an absolute requirement for CD4+ T cells in allogeneic rejection, whereas in others CD4-depleted mice reject certain types of allografts. Moreover, there is evidence that CD8+ T cells are more resistant to immunotherapy and tolerance induction protocols. An intense focal infiltration of mainly CD8+CTLA4+ T lymphocytes during kidney rejection has been described in patients. This suggests that CD8+ T cells could escape from immunosuppression and participate in the rejection process. Our group is primarily interested in the immune mechanisms involved in allograft rejection. Thus, we believe that a better understanding of the role of CD8+ T cells in allograft rejection could indicate new targets for immunotherapy in transplantation. Therefore, the objective of the present review was to focus on the role of the CD8+ T cell population in the rejection of allogeneic tissue.

  19. T-cell exhaustion in tuberculosis: pitfalls and prospects.

    Science.gov (United States)

    Khan, Nargis; Vidyarthi, Aurobind; Amir, Mohammed; Mushtaq, Khurram; Agrewala, Javed Naim

    2017-03-01

    T-cells play an important role in immunity but when these cells are overexposed to specific antigens, their function may decline. This state is usually referred to as exhaustion and the T-cells show reduced proliferation and functions such as cytokine release. T-cell exhaustion has been observed in several cancers as well as in chronic infections such as tuberculosis (TB). In chronic Mycobacterium tuberculosis (Mtb) infection, T-cells may express the exhaustion phenotype and show a progressive loss of secretion of IL-2, IFN-γ and TNF-α. In some cancers and chronic infection models, blocking the exhaustion phenotype can be achieved with the so-called checkpoint inhibitors. This results in tumor control and more effective immunity. However, in the case of TB, the T-cell exhaustion results are quite ambiguous. Hence, there is a need to investigate and explain the contribution of checkpoint at a molecular level to the outcome of events in chronic TB. Such information could help to guide the success of new therapies against chronic TB. This review highlights the mechanism through which T-cells undergo exhaustion and the approaches that can avert such events. This will help to design immunotherapies that can reinvigorate T-cell potency to protect patients from TB.

  20. Regulatory T Cells and Their Role in Animal Disease.

    Science.gov (United States)

    Veiga-Parga, T

    2016-07-01

    In humans and mouse models, Foxp3(+) regulatory T cells are known to control all aspects of immune responses. However, only limited information exists on these cells' role in diseases of other animals. In this review, we cover the most important features and different types of regulatory T cells, which include those that are thymus-derived and peripherally induced, the mechanisms by which they control immune responses by targeting effector T cells and antigen-presenting cells, and most important, their role in animal health and diseases including cancer, infections, and other conditions such as hypersensitivities and autoimmunity. Although the literature regarding regulatory T cells in domestic animal species is still limited, multiple articles have recently emerged and are discussed. Moreover, we also discuss the evidence suggesting that regulatory T cells might limit the magnitude of effector responses, which can have either a positive or negative result, depending on the context of animal and human disease. In addition, the issue of plasticity is discussed because plasticity in regulatory T cells can result in the loss of their protective function in some microenvironments during disease. Lastly, the manipulation of regulatory T cells is discussed in assessing the possibility of their use as a treatment in the future. © The Author(s) 2016.

  1. γδ T-cell immunotherapy for lung cancer.

    Science.gov (United States)

    Yoshida, Yukihiro; Nakajima, Jun; Wada, Hiromi; Kakimi, Kazuhiro

    2011-05-01

    Lung cancer is the leading cause of cancer death worldwide, yet there are still no satisfactory protocols available for treating this disease, emphasizing the urgency for more effective therapies. Recent clinical trials have provided encouraging evidence of the benefits of certain forms of immunotherapy. Here, we summarize recent developments in the area of γδ T-cell therapy for lung cancer in our center. γδ T cells constitute 2%-10% of T lymphocytes in human blood and play a role in immune surveillance against microbial pathogens and, possibly, cancer. These T cells recognize phosphoantigens via polymorphic γδ T-cell antigen receptors (TCR), as well as the major histocompatibility complex (MHC) class I chain-related molecules, A and B (MICA and MICB), via nonpolymorphic NKG2D receptors in an MHC-unrestricted manner. This implies that γδ T cells could retain antitumor effects despite reduced expression of MHC and tumor antigens on cancer cells. Thus, clinical trials have been conducted to evaluate the safety and efficacy of γδ T-cell-based immunotherapies for non-Hodgkin lymphoma, multiple myeloma, and solid tumors. This review focuses on the current status of γδ T-cell-based immunotherapy for lung cancer.

  2. Global transcriptional characterization of CD8+ T cell memory.

    Science.gov (United States)

    Böttcher, Jan; Knolle, Percy A

    2015-02-01

    The differentiation of memory CD8T cells after acute infections comprises generation of functionally distinct populations that either have proliferative potential or display cytotoxic effector functions and that either recirculate into lymphoid tissues or remain tissue-resident. The development of these functionally distinct cell populations is dictated by defined signals from the microenvironment that result in a coordinated expression of a network of transcription factors, which determine the functionality of memory T cells. Distinct transcriptional regulation observed during chronic viral infection that results in generation of T cells that control viral replication in the absence of immunopathology suggests the existence of so far unappreciated functional adaptation of T cell function to the particular need during chronic infections to control infection and avoid immunopathology. Furthermore, the non-canonical generation of CD8T cell memory outside of lymphoid tissues in the liver in the absence of inflammation is correlated with a distinct transcriptional profile and indicates further complexity in the commensurate immune response to infectious pathogens that escape innate immunity. Taken together, distinct profiles of transcriptional regulation are linked to CD8T cells with different functions and provide important mechanistic insight into the continuous functional adaptation of CD8T cells to generate a commensurate immune response to infectious challenges. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

    LENUS (Irish Health Repository)

    Fletcher, J M

    2012-02-01

    Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting gammadelta T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, gammadelta, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

  4. Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming.

    Science.gov (United States)

    Wu, Jiazhu; Xu, Xiaojing; Lee, Eun-Joon; Shull, Austin Y; Pei, Lirong; Awan, Farrukh; Wang, Xiaoling; Choi, Jeong-Hyeon; Deng, Libin; Xin, Hong-Bo; Zhong, Wenxun; Liang, Jinhua; Miao, Yi; Wu, Yujie; Fan, Lei; Li, Jianyong; Xu, Wei; Shi, Huidong

    2016-06-28

    Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.

  5. Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

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    Ciprian Tomuleasa

    2018-02-01

    Full Text Available Chimeric antigen receptor (CAR T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

  6. Structural Elements Recognized by Abacavir-Induced T Cells

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    Daniel Yerly

    2017-07-01

    Full Text Available Adverse drug reactions are one of the leading causes of morbidity and mortality in health care worldwide. Human leukocyte antigen (HLA alleles have been strongly associated with drug hypersensitivities, and the causative drugs have been shown to stimulate specific T cells at the sites of autoimmune destruction. The structural elements recognized by drug-specific T cell receptors (TCRs in vivo are poorly defined. Drug-stimulated T cells express TCRs specific for peptide/HLA complexes, but the characteristics of peptides (sequence, or endogenous or exogenous origin presented in the context of small molecule drugs are not well studied. Using HLA-B*57:01 mediated hypersensitivity to abacavir as a model system, this study examines structural similarities of HLA presented peptides recognized by drug-specific TCRs. Using the crystal structure of HLA-B*57:01 complexed with abacavir and an immunogenic self peptide, VTTDIQVKV SPT5a 976–984, peptide side chains exhibiting flexibility and solvent exposure were identified as potential drug-specific T cell recognition motifs. Viral sequences with structural motifs similar to the immunogenic self peptide were identified. Abacavir-specific T cell clones were used to determine if virus peptides presented in the context of abacavir stimulate T cell responsiveness. An abacavir-specific T cell clone was stimulated by VTQQAQVRL, corresponding to HSV1/2 230–238, in the context of HLA-B*57:01. These data suggest the T cell polyclonal response to abacavir consists of multiple subsets, including T cells that recognize self peptide/HLA-B*57:01 complexes and crossreact with viral peptide/HLA-B*57:01 complexes due to similarity in TCR contact residues.

  7. Role of γδ T cells in mucosal intranet

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    Masafumi Yamamoto

    1999-01-01

    Full Text Available Intraepithelial γδ T cells appear to be an essential regulatory T cell subset for the induction and regulation of humoral and cellular immune responses in the mucosa-associated tissues. These cells form a mucosal internet and intranet with epithelial cells which lead to a reciprocal regulation for activation and cell growth. Removal of the TORS gene (γδ-/- mice results in a reduction of epithelial cell turnover and downregulates the expression of major histocompatibility complex class II molecules on epithelial cells. Epithelial cells are capable of producing interleukin (IL-7 and stem cell factor which can activate mucosal γδ T cells expressing IL-7R and c-kit. Further, cell surface immunoregulatory molecules expressed on epithelial cells inhibit the proliferation and cytokine synthesis of γδ T cells stimulated via the TOR-OD3 complex. Thus, direct cell-to-cell interactions between mucosal γδ T cells and epithelial cells occur via their secreted cytokines and their cell surface immunoregulatory molecules to maintain the homeostatic regulation of the mucosal immune system. γδ-/- mice possess significantly lower numbers of immunoglobulin A (IgA producing cells in mucosa- associated tissues, including intestinal lamina propria and salivary glands, when compared with normal control mice. Furthermore, the levels of antigen- specific IgA B cell responses in γδ-/- mice decreased when they were immunized orally. Mucosal γδ T cells possess an ability to maintain an IgA response in the presence of systemic tolerance. These results clearly indicate that γδ T cells play an important role in the regulation of antigen-specific mucosal IgA responses. Taken together, a triad mucosal lymphocytes intranet which connects among γδ T cells, αβ T cells and IgA B cells is necessary for the induction and regulation of IgA antibody responses in mucosal areas.

  8. Mucorales-Specific T Cells in Patients with Hematologic Malignancies.

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    Leonardo Potenza

    Full Text Available Invasive mucormycosis (IM is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients.By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3% of 204 patients, accounting for 32 (5.3% of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD, showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD: 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD.Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.

  9. Pathogenic CD4+ T cells in patients with asthma.

    Science.gov (United States)

    Muehling, Lyndsey M; Lawrence, Monica G; Woodfolk, Judith A

    2017-12-01

    Asthma encompasses a variety of clinical phenotypes that involve distinct T cell-driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4 + T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, T H 2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of T H 2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell "hubs" are discussed. We also describe advances in understanding the origins of atypical T H 2 cells in asthmatic patients, the role of T H 1 cells and other non-T H 2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell-based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  10. Possible neuroimmunomodulation therapy in T-cell-mediated oral diseases

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    Tsuyoshi Sato

    2015-01-01

    Full Text Available Introduction: Recurrent aphthous stomatitis and oral lichen planus are local chronic inflammatory diseases which are implicated in T cell-mediated immunity. According to the systematic review, there is insufficient evidence to support any specific treatment for T-cell mediated oral diseases. The hypothesis: In this paper, we propose a hypothesis that recurrent aphthous stomatitis and oral lichen planus can be treated with selective α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR agonists. Our hypothesis is supported by the following two facts. First, the pathophysiological conditions, T h 1/T h 17 cell activation and autonomic nervous system dysfunction, are observed in T-cell mediated oral diseases as well as in T-cell mediated systemic diseases such as rheumatoid arthritis. Second, the cholinergic anti-inflammatory pathway is inhibited in systemic T-cell mediated chronic inflammatory diseases. On the other hand, treatment with α7 -nAChR agonists which activate the cholinergic anti-inflammatory pathway suppresses neuroinflammation via inhibition of T h 1/T h 17 responses in animal model of systemic T-cell mediated chronic inflammatory diseases. We thus expect that selective α7 -nAChR agonists will be effective for the treatment of T-cell mediated oral diseases. Evaluation of the hypothesis: To test our hypothesis, we need to develop in vivo mouse model of T-cell mediated oral diseases. To evaluate the therapeutic effect of a selective α7 -nAChR agonist, we choose ABT-107 because of its safety and tolerability. We believe that the selective α7 -nAChR agonist, especially ABT-107, may be a therapeutic drug to treat T-cell mediated oral diseases.

  11. Anaplastic thyroid carcinoma in Denmark 1996-2012

    DEFF Research Database (Denmark)

    Hvilsom, Gitte Bjørn; Londero, Stefano Christian; Hahn, Christoffer Holst

    2018-01-01

    BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the least common but most malignant thyroid cancer. We aimed to examine the characteristics as well as evaluate the incidence, prognostic factors, and if introductio