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Sample records for cd4 enriched cervical

  1. Modulation of cytokines and transcription factors (T-Bet and GATA3 in CD4 enriched cervical cells of Chlamydia trachomatis infected fertile and infertile women upon stimulation with chlamydial inclusion membrane proteins B and C

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    Salhan Sudha

    2009-08-01

    Full Text Available Abstract Background Chlamydial Inclusion membrane proteins (Incs, are involved in biochemical interactions with host cells and infecting Chlamydiae. We have previously reported the role of two Chlamydia trachomatis (CT Incs, namely IncB and IncC in generating host immunity in CT infected women. Emerging data shows involvement of Inc stimulated CD4 positive T cells in aiding host immunity in infected fertile and infertile women through the secretion of interferon gamma. However the lack of data on the intra-cytokine interplay to these Incs in infected cell milieu prompted us to investigate further. Methods A total of 14 CT-positive fertile, 18 CT-positive infertile women and 25 uninfected controls were enrolled in this study. CD8 depleted, CD4 enriched cervical cells were isolated and upon stimulation with IncB and IncC, modulation of cytokines (Interleukin (IL-1 Beta, IL-4, IL-5, IL-6, IL-10, Interferon-gamma, IL-12, IL-23, Tumor Necrosis Factor-alpha and Granulocyte macrophage colony-stimulating factor (GM-CSF and T cell lineage regulating transcription factors T-Bet and GATA3 was determined by real-time reverse-transcriptase (RT-PCR and ELISA. Results Significant higher expression (P Conclusion Overall our data shows that CT IncB and IncC are able to upregulate expression of cytokines, namely interferon-gamma, IL-12, IL-23 and GM-CSF in CT-positive fertile women while expression of IL-1 Beta, IL-4, IL-5, IL-6 and IL-10 were upregulated in CT-positive infertile women. Our study also suggests that Incs are able to modulate expression of T cell lineage determinants indicating their involvement in regulation of immune cells.

  2. CD161+CD4+ T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and Interferon-gamma

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    Yu-Hoi eKang

    2012-11-01

    Full Text Available Hepatitis C virus infection is a major cause of chronic liver disease. CD4+ T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4+ T cells are not well defined. We have previously shown that CD8+ T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22 and IFNγ. We therefore analysed expression of CD161 on CD4+ T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichment of CD161+CD4+ T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4+ T cells. IL-22 and IL-17 secreting CD4+ cells were readily found in the livers of HCV+ and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-γ dual secretors (p=0.02 compared to blood, a result reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161+ expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFNγ and IL-22 in the liver may be particularly significant.

  3. Associação entre a contagem de linfócitos T CD4+ e a gravidade da neoplasia intra-epitelial cervical diagnosticada pela histopatologia em mulheres infectadas pelo HIV Association between CD4+ T-cell count and intraepithelial cervical neoplasia diagnosed by histopathology in HIV-infected women

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    Juliana Barroso Zimmermmann

    2006-06-01

    Full Text Available OBJETIVO: avaliar a associação entre a contagem de linfócitos T CD4+ e a gravidade da neoplasia intra-epitelial cervical em pacientes HIV positivas. MÉTODOS: estudo transversal no qual foram incluídas 87 pacientes infectadas pelo HIV, confirmado por testes sorológicos prévios. Todas eram portadoras do HPV cervical, diagnosticado por meio da reação em cadeia da polimerase. Foram realizados anamnese, exame físico e colposcopia de todas em pacientes. A biópsia do colo uterino foi realizada quando indicada pelo exame colposcópico. Os resultados histopatológicos foram classificados com neoplasia intra-epitelial de baixo grau (NIC I ou de alto grau (NIC II e II. A associação entre a contagem de linfócitos T CD4+ e a gravidade da lesão foi verificada por meio da comparação de médias utilizando a análise da variância (ANOVA. RESULTADOS: entre as 60 pacientes biopsiadas foram encontrados 24 casos (40,0% com NIC I, oito (13,3% NIC II, três (5% NIC III, 14 (23,3% pacientes somente com cervicite crônica e 11 (18,3% apresentando efeito citopático produzido pelo HPV, mas sem perda da polaridade celular. Isso equivale a 35 mulheres com lesão intra-epitelial de baixo grau (NIC I + HPV (58,3% e 11 (18,3% com lesão intra-epitelial de alto grau (NIC II + NIC III. A associação entre a média da contagem de linfócitos T CD4+ e a gravidade da lesão intra-epitelial cervical não foi significativa (p=0,901. CONCLUSÕES: não houve associação entre a contagem de linfócitos T CD4+ e a gravidade da lesão intra-epitelial do colo uterino, diagnosticada pelo exame histopatológico.PURPOSE: to evaluate association between CD4+ cell count and cervical intraepithelial lesion severity in HIV-infected women. METHODS: cross-sectional study of 87 HIV-infected patients which were confirmed by previous serologic examinations. All had cervical HPV diagnosed by polymerase chain reaction (PCR. All patients underwent anamnesis, physical examinations and

  4. Associação entre a contagem de linfócitos T CD4+ e a gravidade da neoplasia intra-epitelial cervical diagnosticada pela histopatologia em mulheres infectadas pelo HIV Association between CD4+ T-cell count and intraepithelial cervical neoplasia diagnosed by histopathology in HIV-infected women

    OpenAIRE

    Juliana Barroso Zimmermmann; Victor Hugo de Melo; Lúcia Porto Fonseca de Castro; Márcio José Martins Alves; Sebastião Guerra Zimmermmann; Dora Mendez Del Castillo

    2006-01-01

    OBJETIVO: avaliar a associação entre a contagem de linfócitos T CD4+ e a gravidade da neoplasia intra-epitelial cervical em pacientes HIV positivas. MÉTODOS: estudo transversal no qual foram incluídas 87 pacientes infectadas pelo HIV, confirmado por testes sorológicos prévios. Todas eram portadoras do HPV cervical, diagnosticado por meio da reação em cadeia da polimerase. Foram realizados anamnese, exame físico e colposcopia de todas em pacientes. A biópsia do colo uterino foi realizada quand...

  5. Relação entre diagnóstico citopatológico de neoplasia intra-epitelial cervical e índices de células CD4+ e de carga viral em pacientes HIV-soropositivas Association of cervical intraepithelial neoplasia with CD4 T cell counts and viral load in HIV-infected women

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    Raquel Autran Coelho

    2004-03-01

    Full Text Available OBJETIVVO: relacionar a gravidade de lesão cervical diagnosticada por exame citopatológico à contagem de células CD4+ e à carga viral de RNA-HIV em pacientes HIV-soropositivas. MÉTODOS: foram avaliadas retrospectivamente, por meio de revisão de prontuários, 115 pacientes HIV-positivas atendidas em ambulatório de hospital universitário, no período de janeiro de 2002 até abril de 2003. Oitenta e três casos apresentaram diagnóstico de neoplasia intra-epitelial cervical (NIC ao exame citopatológico, e trinta e dois, exames sem alterações. Todas as pacientes apresentavam contagem de células CD4+ e carga viral à época do exame. Os casos foram distribuídos quanto ao índice de células CD4+ em três grupos: CD4 acima de 500 cel/mm³, entre 200 e 500 cel/mm³ ou abaixo de 200 cel/mm³, e, em outros três grupos, quanto à carga viral de HIV: menor do que 10.000 cópias RNA-HIV/mL, entre 10.000 e 100.000 cópias RNA-HIV/mL ou maior do que 100.000 cópias RNA-HIV/mL. A verificação da hipótese de associação foi realizada por meio do teste exato de Fisher. RESULTADOS: das 83 pacientes com NIC citopatológico, 73% apresentaram contagem de células CD4+ abaixo de 500 células/mm³. Em qualquer das faixas de contagem de células CD4+, mais da metade das pacientes apresentavam NIC I citopatológico. Quanto à carga viral de HIV, 71,7% das pacientes com menor carga viral de HIV apresentaram NIC I, ao passo que 11,3% revelaram NIC III. Já no grupo com maior carga viral (100.000 cópias/mL, em 61,5% do total de pacientes o exame citopatológico foi compatível com NIC I, e 30,8% com NIC III. CONCLUSÃO: houve evidência de associação entre carga viral e NIC (p=0.013, não sendo observado o mesmo em relação à contagem de linfócitos CD4+. A presença de infecção secundária cervicovaginal foi considerada possível fator confundidor.PURPOSE: to correlate the type of cervical lesion diagnosed by Pap smear with CD4 cell counts and HIV

  6. CD4(+) memory T cells with high CD26 surface expression are enriched for Th1 markers and correlate with clinical severity of multiple sclerosis

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    Krakauer, M; Sorensen, P S; Sellebjerg, F

    An aberrant immune activation is believed to be important in the pathogenesis of multiple sclerosis (MS). Expression of CD4(+) T lymphocyte surface molecules indicative of immune activation and effector functions has been correlated with disease severity and activity. CD4(+) CD45R0(+) CD26(high) ...

  7. CD4 responses against IDO

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    Andersen, Mads Hald

    2012-01-01

    Natural indoleamine-2,3-dioxygenase (IDO)-reactive CD4(+) T cells have been shown to release interferonγ (IFNγ), tumor necrosis factor α (TNFα), as well as interleukin 17 (IL-17). In some individuals, these cells also demonstrated the ability to suppress IL-10 production. IDO-specific CD4(+) helper...

  8. HuMax-CD4

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    Skov, Lone; Kragballe, Knud; Zachariae, Claus;

    2003-01-01

    BACKGROUND: Psoriasis is characterized by infiltration with mononuclear cells. Especially activated memory CD4+ T cells are critical in the pathogenesis. Interaction between the CD4 receptor and the major histocompatibility complex class II molecule is important for T-cell activation. OBJECTIVE: To...... dose level, 6 (38%) of 16 patients obtained more than 25% reduction of PASI and 3 (19%) obtained more than 50% reduction of PASI. A dose-dependent decrease in total lymphocyte count was seen and was parallel to a dose-dependent decrease in CD4+ T cells. This decrease was due to a decrease in the memory...

  9. Conservative Management of Class 4 Invasive Cervical Root Resorption Using Calcium-enriched Mixture Cement.

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    Asgary, Saeed; Nosrat, Ali

    2016-08-01

    Class 4 invasive cervical root resorption (ICRR) presents a treatment dilemma in endodontics. The widely accepted treatment options for a class 4 ICRR are to leave these teeth untreated for as long as they are asymptomatic or extraction. This report presents a conservative approach for the management of class 4 ICRR. A 28-year-old woman was referred for root canal treatment of tooth #26. The patient had a history of orthodontic treatment. Radiographic evaluation showed class 4 ICRR that had perforated the root canal space, a radiolucent crestal bony defect, and a periapical lesion. Clinically, a deep (6-mm) probing area was found on the mesial side of the tooth that bled on probing. The tooth was sensitive to percussion. After the treatment options were discussed with the patient, she chose to save the tooth. After complete chemomechanical preparation of the root canal, the entire canal space and perforation area were filled with calcium-enriched mixture cement. No attempt was made to mechanically remove the resorptive lacuna. Twenty four months after treatment, the tooth was functional and asymptomatic, and probing was within normal limits (canal space with calcium-enriched mixture cement may be a viable treatment option for an otherwise non-treatable tooth with class 4 invasive cervical root resorption. PMID:27316319

  10. CD4+CD25+ Treg cell and Foxp3 expression play key roles in the pathogenesis of cervical carcinoma%宫颈癌患者外周血CD4+CD25+调节性T细胞及其Foxp3表达的临床意义

    Institute of Scientific and Technical Information of China (English)

    徐华; 王丹波

    2015-01-01

    目的 评价宫颈癌患者外周血CD4+CD25+调节性T细胞(Regulatery T cell,Treg)及其Foxp3表达的临床意义.方法 收集中国医科大学附属盛京医院自2012年1月至2013年6月手术治疗的早期宫颈癌患者(FIGO分期≤Ⅱ期)34例,高级别宫颈上皮内瘤变(CIN2/3)患者30例以及20例健康女性作为正常对照.流式细胞技术检测各研究组手术前、后及对照组外周血Treg及Foxp3+ Treg细胞占CD4+T细胞比例,应用t检验和单因素方差法进行统计学分析.结果 比较宫颈癌、CIN2/3及对照组外周血Treg及Foxp3+ Treg细胞所占CD4+T细胞比例,各组间差异有统计学意义(P<0.05);术后早期(7 d),宫颈癌及CIN2/3患者外周血Foxp3+ Treg细胞所占比例较术前显著下降(P<0.05),但Treg细胞所占比例无显著性变化(P>0.05);术后恢复期(1个月),宫颈癌及CIN2/3患者外周血Foxp3+ Treg细胞所占比例较术后早期无显著变化,但Treg细胞所占比例较术后早期显著性降低(P<0.05).结论 宫颈癌患者外周血Treg细胞及其Foxp3的表达均与病变程度相关;Treg细胞Foxp3的表达具有不稳定性;宫颈癌肿瘤微环境可能是维持Treg细胞分化增殖及Foxp3稳定表达的外在客观条件.

  11. Novel Teleost CD4-Bearing Cell Populations Provide Insights into the Evolutionary Origins and Primordial Roles of CD4+ Lymphocytes and CD4+ Macrophages.

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    Takizawa, Fumio; Magadan, Susana; Parra, David; Xu, Zhen; Korytář, Tomáš; Boudinot, Pierre; Sunyer, J Oriol

    2016-06-01

    Tetrapods contain a single CD4 coreceptor with four Ig domains that likely arose from a primordial two-domain ancestor. Notably, teleost fish contain two CD4 genes. Like tetrapod CD4, CD4-1 of rainbow trout includes four Ig domains, whereas CD4-2 contains only two. Because CD4-2 is reminiscent of the prototypic two-domain CD4 coreceptor, we hypothesized that by characterizing the cell types bearing CD4-1 and CD4-2, we would shed light into the evolution and primordial roles of CD4-bearing cells. Using newly established mAbs against CD4-1 and CD4-2, we identified two bona-fide CD4(+) T cell populations: a predominant lymphocyte population coexpressing surface CD4-1 and CD4-2 (CD4 double-positive [DP]), and a minor subset expressing only CD4-2 (CD4-2 single-positive [SP]). Although both subsets produced equivalent levels of Th1, Th17, and regulatory T cell cytokines upon bacterial infection, CD4-2 SP lymphocytes were less proliferative and displayed a more restricted TCRβ repertoire. These data suggest that CD4-2 SP cells represent a functionally distinct population and may embody a vestigial CD4(+) T cell subset, the roles of which reflect those of primeval CD4(+) T cells. Importantly, we also describe the first CD4(+) monocyte/macrophage population in a nonmammalian species. Of all myeloid subsets, we found the CD4(+) population to be the most phagocytic, whereas CD4(+) lymphocytes lacked this capacity. This study fills in an important gap in the knowledge of teleost CD4-bearing leukocytes, thus revealing critical insights into the evolutionary origins and primordial roles of CD4(+) lymphocytes and CD4(+) monocytes/macrophages. PMID:27183628

  12. CD4-regulatory cells in COPD patients

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    Smyth, Lucy J C; Starkey, Cerys; Vestbo, Jørgen;

    2007-01-01

    BACKGROUND: The numbers of airway CD8 and B lymphocytes are increased in COPD patients, suggesting an autoimmune process. CD4-regulatory T cells control autoimmunity but have not been studied in patients with COPD. OBJECTIVE: To compare T-regulatory cell numbers in the BAL from COPD patients......, smokers with normal lung function, and healthy nonsmokers (HNS). METHODS: BAL and peripheral blood mononuclear cell (PBMC) samples were obtained from 26 COPD patients, 19 smokers, and 8 HNS. Flow cytometry was performed for regulatory phenotypic markers. RESULTS: COPD patients had increased BAL CD8...... numbers compared to smokers and HNS. CD4 numbers were similar between groups. There was increased BAL CD4CD25(bright) expression in smokers (median 28.8%) and COPD patients (median 23.1%) compared to HNS (median 0%). Increased FoxP3 expression was confirmed in BAL CD4CD25(bright) cells. BAL CD4CD25 cells...

  13. Predicting AIDS-related events using CD4 percentage or CD4 absolute counts

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    Donabedian Haig

    2006-08-01

    Full Text Available Abstract Background The extent of immunosuppression and the probability of developing an AIDS-related complication in HIV-infected people is usually measured by the absolute number of CD4 positive T-cells. The percentage of CD4 positive cells is a more easily measured and less variable number. We analyzed sequential CD4 and CD8 numbers, percentages and ratios in 218 of our HIV infected patients to determine the most reliable predictor of an AIDS-related event. Results The CD4 percentage was an unsurpassed predictor of the occurrence of AIDS-related events when all subsets of patients are considered. The CD4 absolute count was the next most reliable, followed by the ratio of CD4/CD8 percentages. The value of CD4 percentage over the CD4 absolute count was seen even after the introduction of highly effective HIV therapy. Conclusion The CD4 percentage is unsurpassed as a parameter for predicting the onset of HIV-related diseases. The extra time and expense of measuring the CD4 absolute count may be unnecessary.

  14. Role of Gag and lipids during HIV-1 assembly in CD4 T cells and Macrophages

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    DelphineMMuriaux; PhilippeBenaroch

    2014-01-01

    HIV-1 is an RNA enveloped virus that preferentially infects CD4+ T lymphocytes and also macrophages. In CD4+ T cells, HIV-1 mainly buds from the host cell plasma membrane. The viral Gag polyprotein targets the plasma membrane and is the orchestrator of the HIV assembly as its expression is sufficient to promote the formation of virus-like particles particles carrying a lipidic envelope deriving from the host cell membrane. Certain lipids are enriched in the viral...

  15. CD4(+)CD25 (+)CD127 (low/-) T cells: a more specific Treg population in human peripheral blood.

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    Yu, Ning; Li, Xiaomei; Song, Weiya; Li, Dongmei; Yu, Daliang; Zeng, Xiaofeng; Li, Mengtao; Leng, Xiaomei; Li, Xiangpei

    2012-12-01

    The quantitative identification and enrichment of viable regulatory T cells (Treg) requires reliable surface markers that are selectively expressed on Treg. Foxp3 is the accepted marker of nTreg, but it cannot be used to isolate cells for functional studies. In this study, we compared four staining profiles of Treg, including CD4(+)CD25(high) T cells, CD4(+)CD39(+) T cells, CD4(+)CD73(+) T cells, and CD4(+)CD25(+)CD127(low/-) T cells. We found that CD4(+)CD25(+)CD127(low/-) T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4(+)CD25(+)Foxp3(+) T cells, the accepted identifying characteristics for "real" nTreg cells. Moreover, functional data showed that CD4(+)CD25(+)CD127(low/-) T cells could effectively suppress the proliferation of CD4(+)CD25(-) T cells, suggesting that compared with the other three populations, CD4(+)CD25(+)CD127(low/-) T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood. Finally, we showed that CD4(+)CD25(+)CD127(low/-) can be used to quantitate Treg cells in individuals with systemic lupus erythematosus supporting the use of CD4(+)CD25(+)CD127(low/-) to identify human Treg cells. PMID:22752562

  16. Idiopathic CD4 lymphocytopenia with sensorimotor polyneuropathy.

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    Puri, Vinod; Duggal, Ashish Kumar; Chaudhry, Neera

    2016-01-01

    A, 21-years-old, male, presented with acute onset, gradually progressive, predominantly distal, symmetrical weakness of both upper and lower limbs with arreflexia. He had impaired sensations in glove and stocking distribution with distal gradient. He was found to have absolute CD4 + cell count of 188 cells/μL, absolute CD8 cell count, 532 cells/μL and CD4: CD8 ratio of 0.35. Electrophysiology revealed reduced to absent CMAP amplitude as well as SNAPs in various nerves of upper and lower limbs, along with normal conduction velocity and normal F wave latencies. Pattern evoked visual potentials were prolonged, on both sides, P100 being 130 ms, on right and 108 ms, on left side. In the follow up of 2 years, he showed spontaneous but gradual clinical improvement but his electrophysiological parameters as well as CD 4+ cells count did not show any significant improvement. PMID:27570393

  17. Idiopathic CD4 lymphocytopenia with sensorimotor polyneuropathy

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    Vinod Puri

    2016-01-01

    Full Text Available A, 21-years-old, male, presented with acute onset, gradually progressive, predominantly distal, symmetrical weakness of both upper and lower limbs with arreflexia. He had impaired sensations in glove and stocking distribution with distal gradient. He was found to have absolute CD4 + cell count of 188 cells/μL, absolute CD8 cell count, 532 cells/μL and CD4: CD8 ratio of 0.35. Electrophysiology revealed reduced to absent CMAP amplitude as well as SNAPs in various nerves of upper and lower limbs, along with normal conduction velocity and normal F wave latencies. Pattern evoked visual potentials were prolonged, on both sides, P100 being 130 ms, on right and 108 ms, on left side. In the follow up of 2 years, he showed spontaneous but gradual clinical improvement but his electrophysiological parameters as well as CD 4+ cells count did not show any significant improvement.

  18. Cd4As2Br3

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    Mohammed Kars

    2014-03-01

    Full Text Available Single crystals of Cd4As2Br3 (tetracadmium biarsenide tribromide were grown by a chemical transport reaction. The structure is isotypic with the members of the cadmium and mercury pnictidohalides family with general formula M4A2X3 (M = Cd, Hg; A = P, As, Sb; X = Cl, Br, I and contains two independent As atoms on special positions with site symmetry -3 and two independent Cd atoms, of which one is on a special position with site symmetry -3. The Cd4As2Br3 structure consists of AsCd4 tetrahedra sharing vertices with isolated As2Cd6 octahedra that contain As–As dumbbells in the centre of the octahedron. The Br atoms are located in the voids of this three-dimensional arrangement and bridge the different polyhedra through Cd...Br contacts.

  19. CD4-regulatory cells in COPD patients

    DEFF Research Database (Denmark)

    Smyth, Lucy J C; Starkey, Cerys; Vestbo, Jørgen; Singh, Dave

    2007-01-01

    BACKGROUND: The numbers of airway CD8 and B lymphocytes are increased in COPD patients, suggesting an autoimmune process. CD4-regulatory T cells control autoimmunity but have not been studied in patients with COPD. OBJECTIVE: To compare T-regulatory cell numbers in the BAL from COPD patients, smo...

  20. In Vitro Immune Toxicity of Depleted Uranium: Effects on Murine Macrophages, CD4+ T Cells, and Gene Expression Profiles

    OpenAIRE

    Wan, Bin; Fleming, James T.; Schultz, Terry W.; Sayler, Gary S.

    2005-01-01

    Depleted uranium (DU) is a by-product of the uranium enrichment process and shares chemical properties with natural and enriched uranium. To investigate the toxic effects of environmental DU exposure on the immune system, we examined the influences of DU (in the form of uranyl nitrate) on viability and immune function as well as cytokine gene expression in murine peritoneal macrophages and splenic CD4+ T cells. Macrophages and CD4+ T cells were exposed to various concentrations of DU, and cel...

  1. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development.

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    Seung-Joo Lee

    2012-01-01

    Full Text Available Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo.

  2. Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

    International Nuclear Information System (INIS)

    Highlights: ► Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. ► We hypothesize that CD4i antibodies could induce conformational changes in gp120. ► CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. ► CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibit decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.

  3. Effector CD4 and CD8 T Cells and Their Role in the Tumor Microenvironment

    DEFF Research Database (Denmark)

    Hadrup, Sine; Donia, Marco; thor Straten, Per

    2012-01-01

    with colo-rectal cancer (CRC), and also for others solid cancers. These data goes hand in hand with studies of clonality of TIL showing the T cells among TIL are expanded clonally, and also that tumor specific T cells of CD4 as well as CD8 type are enriched at the tumor site. The tumor microenvironment...

  4. Role of Gag and lipids during HIV-1 assembly in CD4+ T cells and macrophages

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    Mariani, Charlotte; Desdouits, Marion; Favard, Cyril; Benaroch, Philippe; Muriaux, Delphine M.

    2014-01-01

    HIV-1 is an RNA enveloped virus that preferentially infects CD4+ T lymphocytes and also macrophages. In CD4+ T cells, HIV-1 mainly buds from the host cell plasma membrane. The viral Gag polyprotein targets the plasma membrane and is the orchestrator of the HIV assembly as its expression is sufficient to promote the formation of virus-like particles carrying a lipidic envelope derived from the host cell membrane. Certain lipids are enriched in the viral membrane and are thought to play a key r...

  5. Blocking interaction of viral gp120 and CD4-expressing T cells by single-stranded DNA aptamers

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    Zhao, Nianxi; Pei, Sung-nan; Parekh, Parag; Salazar, Eric; Zu, Youli

    2014-01-01

    To investigate the potential clinical application of aptamers to prevention of HIV infection, single- stranded DNA (ssDNA) aptamers specific for CD4 were developed using the systematic evolution of ligands by exponential enrichment approach and next generation sequencing. In contrast to RNA-based aptamers, the developed ssDNA aptamers were stable in human serum up to 12 hr. Cell binding assays revealed that the aptamers specifically targeted CD4-expressing cells with high binding affinity (Kd...

  6. In vitro separation and expansion of CD4 lymphocytes from HIV-infected individuals without activation of HIV infection

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    Nielsen, S D; Nielsen, Jens Ole; Hansen, J E

    1997-01-01

    In order to offer a gene therapy-based treatment against AIDS, it is likely to be necessary to harvest and culture CD4 cells from HIV-positive patients without activating the HIV infection. We have used a magnetic cell sorting (MACS) system to enrich CD4 cells. Using positive selection, CD4 cells...... from a total of 14 patients were enriched from a mean percentage of CD4 cells in PBMC of 18% to 91% CD4 cells in the enriched cell fraction. Furthermore, we found that this separation did not lead to an increase in viral load. The MACS performed equally well on cells from HIV-positive patients and HIV...... expression and no loss of polyclonality. Only in two of six cultures were we able to detect HIV-antigen production,and using an LTR-PCR and an RT assay, we did not find activation of the HIV infection during the culture period. Thus, the method described separates and expands CD4 cells from HIV...

  7. In vitro separation and expansion of CD4 lymphocytes from HIV-infected individuals without activation of HIV infection

    DEFF Research Database (Denmark)

    Nielsen, S D; Nielsen, Jens Ole; Hansen, J E

    1997-01-01

    In order to offer a gene therapy-based treatment against AIDS, it is likely to be necessary to harvest and culture CD4 cells from HIV-positive patients without activating the HIV infection. We have used a magnetic cell sorting (MACS) system to enrich CD4 cells. Using positive selection, CD4 cells...... from a total of 14 patients were enriched from a mean percentage of CD4 cells in PBMC of 18% to 91% CD4 cells in the enriched cell fraction. Furthermore, we found that this separation did not lead to an increase in viral load. The MACS performed equally well on cells from HIV-positive patients and HIV...... expression and no loss of polyclonality. Only in two of six cultures were we able to detect HIV-antigen production, and using an LTR-PCR and an RT assay, we did not find activation of the HIV infection during the culture period. Thus, the method described separates and expands CD4 cells from HIV...

  8. CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity

    International Nuclear Information System (INIS)

    CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n = 16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.

  9. Analysis of purine metabolic enzymes in human CD4 Leu 8- and CD4 Leu 8+ lymphocyte subpopulations.

    Science.gov (United States)

    Fernandez-Mejia, C; Polmar, S H; Peralta-Zaragoza, O; Madrid-Marina, V

    1993-02-01

    1. Specific activities of adenosine deaminase, purine nucleoside phosphorylase, adenosine kinase, 5'-nucleotidase, S-adenosyl-L-homocysteine hydrolase, AMP deaminase, adenine phosphoribosyl transferase, and hypoxanthine phosphoribosyl transferase were analyzed in human CD4 T-lymphocyte subsets. 2. CD4 Leu 8- (helper/inducer) and CD4 Leu 8+ (suppressor/inducer) subpopulations were obtained by panning or fluorescence activated cell sorting techniques using specific monoclonal antibodies. 3. A 45% decrease of 5'-NT AMP activity in the CD4 Leu 8- cells (suppressor/inducer) compared with CD4 total cell population. 4. No statistical significant differences in enzyme activity were found between the subsets analyzed in other purine enzymes. 5. These results suggest that the distribution of purine metabolic enzymes is homogeneous in CD4 Leu 8- and CD4 Leu 8+ T-lymphocyte subpopulations. PMID:8444317

  10. Different thresholds of T cell activation regulate FIV infection of CD4+CD25+ and CD4+CD25- cells

    International Nuclear Information System (INIS)

    Cellular activation plays an important role in retroviral replication. Previously, we have shown that CD4+CD25+ T cells by the virtue of their partially activated phenotype represent ideal candidates for a productive feline immunodeficiency virus (FIV) infection. In the present study, we extended our previous observations with regard to FIV replication in CD4+CD25+ and CD4+CD25- cells under different stimulation conditions. Both CD4+CD25+ and CD4+CD25- cells remain latently infected in the absence of IL-2 or concanvalinA (ConA), respectively; harboring a replication competent provirus capable of reactivation several days post-infection. While CD4+CD25+ cells require low levels of exogenous IL-2 and virus inputs for an efficient FIV replication, CD4+CD25- T cells can only be productively infected in the presence of either high concentrations of IL-2 or high virus titers, even in the absence of mitogenic stimulation. Interestingly, while high virus input activates CD4+CD25- cells to replicate FIV, it induces apoptosis in a high percentage of CD4+CD25+ T cells. High IL-2 concentrations but not high virus inputs lead to surface upregulation of CD25 and significant cellular proliferation in CD4+CD25- cells. These results suggest that CD4+CD25+ and CD4+CD25- T cells have different activation requirements which can be modulated by both viral and cytokine stimuli to reach threshold activation levels in order to harbor a productive FIV infection. This holds implications in vivo for CD4+CD25+ and CD4+CD25- cells to serve as potential reservoirs of a productive and latent FIV infection

  11. Regulation and gene expression profiling of NKG2D positive human cytomegalovirus-primed CD4+ T-cells.

    Directory of Open Access Journals (Sweden)

    Helle Jensen

    Full Text Available NKG2D is a stimulatory receptor expressed by natural killer (NK cells, CD8(+ T-cells, and γδ T-cells. NKG2D expression is normally absent from CD4(+ T-cells, however recently a subset of NKG2D(+ CD4(+ T-cells has been found, which is specific for human cytomegalovirus (HCMV. This particular subset of HCMV-specific NKG2D(+ CD4(+ T-cells possesses effector-like functions, thus resembling the subsets of NKG2D(+ CD4(+ T-cells found in other chronic inflammations. However, the precise mechanism leading to NKG2D expression on HCMV-specific CD4(+ T-cells is currently not known. In this study we used genome-wide analysis of individual genes and gene set enrichment analysis (GSEA to investigate the gene expression profile of NKG2D(+ CD4(+ T-cells, generated from HCMV-primed CD4(+ T-cells. We show that the HCMV-primed NKG2D(+ CD4(+ T-cells possess a higher differentiated phenotype than the NKG2D(- CD4(+ T-cells, both at the gene expression profile and cytokine profile. The ability to express NKG2D at the cell surface was primarily determined by the activation or differentiation status of the CD4(+ T-cells and not by the antigen presenting cells. We observed a correlation between CD94 and NKG2D expression in the CD4(+ T-cells following HCMV stimulation. However, knock-down of CD94 did not affect NKG2D cell surface expression or signaling. In addition, we show that NKG2D is recycled at the cell surface of activated CD4(+ T-cells, whereas it is produced de novo in resting CD4(+ T-cells. These findings provide novel information about the gene expression profile of HCMV-primed NKG2D(+ CD4(+ T-cells, as well as the mechanisms regulating NKG2D cell surface expression.

  12. Canine CD4(+)CD8(+) double-positive T cells can develop from CD4(+) and CD8(+) T cells.

    Science.gov (United States)

    Bismarck, Doris; Moore, Peter F; Alber, Gottfried; von Buttlar, Heiner

    2014-12-15

    For a long time the expression of the CD4 and CD8 receptor on peripheral blood T cells was thought to be mutually exclusive. However, in canine peripheral blood, similar to other species as swine or human for example, mature CD4(+)CD8(+) double-positive (dp) T cells exist which simultaneously express both surface receptors and have features of activated T cells. Canine CD4(+)CD8(+)dp T cells are heterogeneous and can be divided into three subpopulations by their intensity of CD4 and CD8α expression: CD4(bright)CD8α(bright), CD4(dim)CD8α(bright) and CD4(dim)CD8α(dim). The number of CD4(+)CD8α(+)dp T cells increases after in vitro stimulation of canine peripheral blood mononuclear cells (PBMC) raising the question of their progenitor(s). Thus, the aim of our study was to characterize the progenitor(s) of canine CD4(+)CD8α(+)dp T cells. By cell tracing experiments we identified both CD4(+) single-positive (sp) and also CD8α(+)sp T cells as progenitors of canine CD4(+)CD8α(+)dp T cells after in vitro stimulation. CD4(+)sp T cells almost exclusively upregulate a CD8αα homodimer, whereas CD8α(+)sp T cells can become CD4(+)CD8αβ(+) or CD4(+)CD8αα(+). Even in the absence of other cells, highly purified CD4(+)sp T cells can become double-positive upon in vitro stimulation, whereas highly purified CD8α(+)sp T cells fail to do so. However, CD8α(+)sp T cells can additionally express CD4 when stimulated in the presence of CD4(-)CD8α(-) double-negative (dn) cells or more efficiently when stimulated in the presence of CD4(+)sp T cells. Soluble factors secreted by CD4(+)sp T cells are sufficient for the upregulation of CD4 on CD8α(+)sp T cells, but direct cell-cell contact between CD4(+)sp and CD8α(+)sp T cells is more efficient. mRNA analysis shows that additional CD4 expression on CD8α(+)sp T cells results from de novo synthesis. Thus, uptake of soluble CD4 or trogocytosis is less likely as mechanism for generation of canine double-positive T cells. CD4(+)CD

  13. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung-Chang [National Institute of Health, Chungbuk (Korea, Republic of); School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Hyeon Guk [National Institute of Health, Chungbuk (Korea, Republic of); Roh, Tae-Young [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Park, Jihwan [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Jung, Kyung-Min; Lee, Joo-Shil [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Sang-Yun [School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Sung Soon [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Byeong-Sun, E-mail: byeongsun@korea.kr [National Institute of Health, Chungbuk (Korea, Republic of)

    2011-01-14

    Research highlights: {yields} CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. {yields} CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. {yields} HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. {yields} H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. {yields} HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56{sup Lck}, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56{sup Lck}, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new

  14. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    International Nuclear Information System (INIS)

    Research highlights: → CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. → CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. → HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. → H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. → HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56Lck, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56Lck, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.

  15. Effector CD4+ T cell expression signatures and immune-mediated disease associated genes.

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    Full Text Available Genome-wide association studies (GWAS in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune-mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20 compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2, where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis.

  16. HIV, TB and ART: the CD4 enigma

    OpenAIRE

    Williams, Brian; Gouws, Eleanor

    2012-01-01

    The concentration of CD4 T-lymphocytes (CD4 count), in a person's plasma is widely used to decide when to start HIV-positive people on anti-retroviral therapy (ART) and to predict the impact of ART on the future course of HIV and tuberculosis (TB). However, CD4 cell-counts vary widely within and among populations and depend on many factors besides HIV-infection. The way in which CD4 counts decline over the course of HIV infection is neither well understood nor widely agreed. We review what is...

  17. Allergen-Specific CD4(+) T Cells in Human Asthma.

    Science.gov (United States)

    Ling, Morris F; Luster, Andrew D

    2016-03-01

    In allergic asthma, aeroallergen exposure of sensitized individuals mobilizes robust innate and adaptive airway immune responses, stimulating eosinophilic airway inflammation and the activation and infiltration of allergen-specific CD4(+) T cells into the airways. Allergen-specific CD4(+) T cells are thought to be central players in the asthmatic response as they specifically recognize the allergen and initiate and orchestrate the asthmatic inflammatory response. In this article, we briefly review the role of allergen-specific CD4(+) T cells in the pathogenesis of human allergic airway inflammation in allergic individuals, discuss the use of allergen-major histocompatibility complex class II tetramers to characterize allergen-specific CD4(+) T cells, and highlight current gaps in knowledge and directions for future research pertaining to the role of allergen-specific CD4(+) T cells in human asthma. PMID:27027948

  18. Isolation and Characterization of Salmonid CD4+ T Cells.

    Science.gov (United States)

    Maisey, Kevin; Montero, Ruth; Corripio-Miyar, Yolanda; Toro-Ascuy, Daniela; Valenzuela, Beatriz; Reyes-Cerpa, Sebastián; Sandino, Ana María; Zou, Jun; Wang, Tiehui; Secombes, Christopher J; Imarai, Mónica

    2016-05-15

    This study reports the isolation and functional characterization of rainbow trout (Oncorhynchus mykiss) CD4-1(+) T cells and the establishment of an IL-15-dependent CD4-1(+) T cell line. By using Abs specific for CD4-1 and CD3ε it was possible to isolate the double-positive T cells in spleen and head kidney. The morphology and the presence of transcripts for T cell markers in the sorted CD4-1(+)CD3ε(+) cells were studied next. Cells were found to express TCRα, TCRβ, CD152 (CTLA-4), CD154 (CD40L), T-bet, GATA-3, and STAT-1. The sorted CD4-1(+) T cells also had a distinctive functional attribute of mammalian T lymphocytes, namely they could undergo Ag-specific proliferation, using OVA as a model Ag. The OVA-stimulated cells showed increased expression of several cytokines, including IFN-γ1, IL-4/13A, IL-15, IL-17D, IL-10, and TGF-β1, perhaps indicating that T cell proliferation led to differentiation into distinct effector phenotypes. Using IL-15 as a growth factor, we have selected a lymphoid cell line derived from rainbow trout head kidney cells. The morphology, cell surface expression of CD4-1, and the presence of transcripts of T cell cytokines and transcription factors indicated that this is a CD4-1(+) T cell line. To our knowledge, this is the first demonstration of the presence of CD4-1(+)CD3ε(+) T cells in salmonids. As in mammals, CD4-1(+) T cells may be the master regulators of immune responses in fish, and therefore these findings and the new model T cell line developed will contribute to a greater understanding of T cell function and immune responses in teleost fish. PMID:27053758

  19. Comparative contribution of CD1 on the development of CD4+ and CD8+ T cell compartments.

    Science.gov (United States)

    Wang, B; Chun, T; Wang, C R

    2000-01-15

    CD1 molecules are MHC class I-like glycoproteins whose expression is essential for the development of a unique subset of T cells, the NK T cells. To evaluate to what extent CD1 contributes to the development of CD4+ and CD8+ T cells, we generated CD1oIIo and CD1oTAPo mice and compared the generation of T cells in these double-mutant mice and IIo or TAPo mice. FACS analysis showed that the number of CD4+ T cells in CD1oIIo mice was reduced significantly compared with the corresponding population in IIo mice. Both CD4+ NK1.1+ and the CD4+ NK1.1- population were reduced in CD1oIIo mice, suggesting that CD1 can select not only CD4+ NK1.1+ T cells but also some NK1.1- CD4+ T cells. Functional analysis showed that the residual CD4+ cells in CD1oIIo can secrete large amounts of IFN-gamma and a significant amount of IL-4 during primary stimulation with anti-CD3, suggesting that this population may be enriched for NK T cells restricted by other class I molecules. In contrast to the CD4+ population, no significant differences in the CD8+ T cell compartment can be detected between TAPo and CD1oTAPo mice in all lymphoid tissues tested, including intestinal intraepithelial lymphocytes. Our data suggest that, unlike other MHC class I molecules, CD1 does not contribute in a major way to the development of CD8+ T cells. PMID:10623818

  20. CD4+/CD8+ double-positive T cells

    DEFF Research Database (Denmark)

    Overgaard, Nana H; Jung, Ji-Won; Steptoe, Raymond J;

    2015-01-01

    lymphoid tissues of numerous species, as well as in numerous disease settings, including cancer. The expression of CD4 and CD8 is regulated by a very strict transcriptional program involving the transcription factors Runx3 and ThPOK. Initially thought to be mutually exclusive within CD4(+) and CD8(+) T...... 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....

  1. Adoptive immunotherapy of cancer using CD4+ T cells

    OpenAIRE

    Muranski, Pawel; Restifo, Nicholas P

    2009-01-01

    CD4+ T cells are central to the function of the immune system but their role in tumor immunity remains underappreciated. It is becoming clear that there is an enormous diversity of CD4+ T cell polarization patterns including Th1, Th2, Th17, and regulatory T cells (Tregs). These functionally divergent T cell subsets can have opposing effects — they can trigger tumor rejection or inhibit treatment after adoptive cell transfer. Some polarized CD4+ cells have plasticity, and their phenotypes and ...

  2. Neospora caninum-infected cattle develop parasite-specific CD4+ cytotoxic T lymphocytes.

    Science.gov (United States)

    Staska, Lauren M; McGuire, Travis C; Davies, Christopher J; Lewin, Harris A; Baszler, Timothy V

    2003-06-01

    Cattle infected with Neospora caninum readily experience transplacental parasite transmission, presumably after maternal parasitemia, leading to abortion or birth of congenitally infected calves. Cytotoxic T lymphocytes (CTL) are important mediators of protective immunity against Toxoplasma gondii, an intracellular apicomplexan protozoan closely related to N. caninum. In this study, N. caninum-specific CTL expanded from peripheral blood mononuclear cells of two major histocompatibility complex-mismatched, experimentally infected cattle were identified by using a (51)Cr release cytotoxicity assay. Enrichment and blocking of CD4(+)- and CD8(+)-T-lymphocyte effector subsets indicated that CD4(+) CTL killed N. caninum-infected, autologous target cells and that killing was mediated through a perforin/granzyme pathway. Detection and characterization of CTL responses to N. caninum in the natural, outbred, bovine host will facilitate identification of immunogens and design of immunization strategies to induce parasite-specific CTL against transplacental N. caninum transmission in cattle. PMID:12761108

  3. Multidimensional Clusters of CD4+T Cell Dysfunction Are Primarily Associated with the CD4/CD8 Ratio in Chronic HIV Infection

    DEFF Research Database (Denmark)

    Frederiksen, Juliet Wairimu; Buggert, Marcus; Noyan, Kajsa;

    2015-01-01

    correlation analyses between laboratory parameters and pathological CD4+ clusters revealed that the CD4/CD8 ratio was the preeminent surrogate marker of CD4+ T cells dysfunction using all three methods. Increased frequencies of an early-differentiated CD4+ T cell cluster with high CD38, HLA-DR and PD-1...

  4. 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; Barouch, Dan H.

    2016-01-01

    CD4+ T cell help is critical for optimal CD8+ T cell memory differentiation and maintenance in many experimental systems. Additionally, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced antigen or pathogen clearance. Here 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 days 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

  5. CD4+ T cell responses in hepatitis C virus infection

    Institute of Scientific and Technical Information of China (English)

    Nasser Semmo; Paul Klenerman

    2007-01-01

    Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are relatively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type Ⅰ profile, which promotes cellular effector mechanisms are thought to be more likely to experience viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells,especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in determining the outcome of acute and chronic HCV infection will be discussed in this review.

  6. Adoptive immunotherapy via CD4+ versus CD8+ T cells

    Directory of Open Access Journals (Sweden)

    Vy Phan-Lai

    2016-04-01

    Full Text Available The goal of cancer immunotherapy is to induce specific and durable antitumor immunity. Adoptive T cell therapy (ACT has garnered wide interest, particularly in regard to strategies to improve T cell efficacy in trials. There are many types of T cells (and subsets which can be selected for use in ACT. CD4+ T cells are critical for the regulation, activation and aid of host defense mechanisms and, importantly, for enhancing the function of tumor-specific CD8+ T cells. To date, much research in cancer immunotherapy has focused on CD8+ T cells, in melanoma and other cancers. Both CD4+ T cells and CD8+ T cells have been evaluated as ACT in mice and humans, and both are effective at eliciting antitumor responses. IL-17 producing CD4+ T cells are a new subset of CD4+ T cells to be evaluated in ACT models. This review discusses the benefits of adoptive immunotherapy mediated by CD8+ and CD4+ cells. It also discusses the various type of T cells, source of T cells, and ex vivo cytokine growth factors for augmenting clinical efficacy of ACT. [Biomed Res Ther 2016; 3(4.000: 588-595

  7. Differentiation of Effector CD4 T Cell Populations*

    OpenAIRE

    Zhu, Jinfang; Yamane, Hidehiro; Paul, William E.

    2010-01-01

    CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and r...

  8. Dysregulation of complement system and CD4+ T cell activation pathways implicated in allergic response.

    Directory of Open Access Journals (Sweden)

    Alexessander Couto Alves

    Full Text Available Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13 and of the Th2 master regulator (GATA3, suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1 are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

  9. Cellular plasticity of CD4+ T cells in the intestine

    Directory of Open Access Journals (Sweden)

    Verena eBrucklacher-Waldert

    2014-10-01

    Full Text Available Barrier sites such as the gastrointestinal tract are in constant contact with the environment which contains both beneficial and harmful components. The immune system at the epithelia must make the distinction between these components to balance tolerance, protection and immunopathology. This is achieved via multifaceted immune recognition, highly organised lymphoid structures and the interaction of many types of immune cells. The adaptive immune response in the gut is orchestrated by CD4+ helper T (Th cells which are integral to gut immunity. In recent years it has become apparent that the functional identity of these Th cells is not as fixed as initially thought. Plasticity in differentiated T cell subsets has now been firmly established, in both health and disease. The gut, in particular, utilises CD4+ T cell plasticity to mould CD4+ T cell phenotypes to maintain its finely poised balance of tolerance and inflammation and to encourage biodiversity within the enteric microbiome. In this review we will discuss intestinal helper T cell plasticity and our current understanding of its mechanisms, including our growing knowledge of an evolutionarily ancient symbiosis between microbiota and malleable CD4+ T cell effectors.

  10. Biomarkers of CD4+ CTL cell Mediated Immunity to Tuberculosis

    Science.gov (United States)

    The immune responses mediated by interactions between T-lymphocyte subsets and mycobacteria-infected macrophages are critical for control of tuberculosis. In these studies, the bovine model was used to characterize the cytolytic and mycobactericidal CD4+ T cell response induced by BCG vaccination. ...

  11. Human rotavirus specific T cells: quantification by ELISPOT and expression of homing receptors on CD4+ T cells

    International Nuclear Information System (INIS)

    Using an intracellular cytokine assay, we recently showed that the frequencies of rotavirus (RV)-specific CD4+ and CD8+ T cells secreting INFγ, circulating in RV infected and healthy adults, are very low compared to the frequencies of circulating cytomegalovirus (CMV) reactive T cells in comparable individuals. In children with acute RV infection, these T cells were barely or not detectable. In the present study, an ELISPOT assay enabled detection of circulating RV-specific INFγ-secreting cells in children with RV diarrhea but not in children with non-RV diarrhea without evidence of a previous RV infection. Using microbead-enriched CD4+ and CD8+ T cell subsets, IFNγ-secreting RV-specific CD8+ but not CD4+ T cells were detected in recently infected children. Using the same approach, both CD4+ and CD8+ RV-specific T cells were detected in healthy adults. Furthermore, stimulation of purified subsets of PBMC that express lymphocyte homing receptors demonstrated that RV-specific INFγ-secreting CD4+ T cells from adult volunteers preferentially express the intestinal homing receptor α4β7, but not the peripheral lymph node homing receptor L-selectin. In contrast, CMV-specific INFγ-secreting CD4+ T cells preferentially express L-selectin but not α4β7. These results suggest that the expression of homing receptors on virus-specific T cells depends on the organ where these cells were originally stimulated and that their capacity to secrete INFγ is independent of the expression of these homing receptors

  12. Depletion of CD4+CD25+ regulatory T cells can promote local immunity to suppress tumor growth in benzo[a]pyrene-induced forestomach carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Chen; Jung-Hua Fang; Ming-Derg Lai; Yan-Shen Shan

    2008-01-01

    AIM: To elucidate the distribution of CD4+CD25+ regulatory T cells (Tregs) in different lymphoid tissues and its local enhancement on tumor growth before and after depletion of CD4+CD25+ Tregs.METHODS: Female ICR mice were gavaged with benzo[a]pyrene (BaP) to induce forestomach carcinoma. CD4+CD25+ Tregs were intraperitoneally depleted with monoclonal antibody PC61. These mice were divided into BaP-only, BaP+IgG, BaP+PC61, and control groups. The forestomach of mice was dissected for histological analysis, and tunnel test was performed for apoptosis of tumor cells. CD4+CD25+ Tregs were sorted from different lymphoid tissues and expression of Foxp3, IL-10, and chemokine receptors was analyzed by flow cytometry, semi-quantitative and real-time polymerase chain reaction.RESULTS: The mice gavaged with only BaP showed increased forestomach papilloma and carcinoma at wk 16 and 32. The proportion of CD4+CD25+ Tregs was significantly higher in peri-stomach regional lymph nodes than in other lymphoid tissues. These CD4+CD25+ Tregs in regional lymph nodes expressed higher levels of Foxp3 and IL-10, enriched in the CD62L-subset, and CCR1 and CCR5 chemokine receptors. In mice gavaged with BaP+PC61, the number of tumor nodules and tumor volume decreased significantly with massive infiltrating cells and apoptosis of tumor cells. In the draining regional lymph nodes, the number of CD4+CD25+ Tregs also decreased significantly.CONCLUSION: Inducible and activated CD4+CD25+ Tregs in the draining regional lymph nodes suppress host local immunity during tumor growth. Depletion of CD4+CD25+ Tregs can promote host local immunity to suppress tumor growth.

  13. Cervical dysplasia

    Science.gov (United States)

    ... by your provider. Make sure to get the HPV vaccine when it is offered to you. This vaccine prevents many cervical cancers. ... Early diagnosis and prompt treatment cures most cases of cervical ... severe cervical dysplasia may change into cervical cancer.

  14. Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy

    Directory of Open Access Journals (Sweden)

    Campbell James J

    2006-07-01

    Full Text Available Abstract Background Circulating memory T cells can be divided into tissue-specific subsets, which traffic through distinct tissue compartments during physiologic immune surveillance, based on their expression of adhesion molecules and chemokine receptors. We reasoned that a bias (either enrichment or depletion of CSF T cell expression of known organ-specific trafficking determinants might suggest that homing of T cells to the subarachnoid space could be governed by a CNS-specific adhesion molecule or chemokine receptor. Results The expression of cutaneous leukocyte antigen (CLA and CC-chemokine receptor 4 (CCR4; associated with skin-homing as well as the expression of integrin α4β7 and CCR9 (associated with gut-homing was analyzed on CD4+ memory T cells in CSF from individuals with non-inflammatory neurological diseases using flow cytometry. CSF contained similar proportions of CD4+ memory T cells expressing CLA, CCR4, integrin α4β7 and CCR9 as paired blood samples. Conclusion The results extend our previous findings that antigen-experienced CD4+ memory T cells traffic through the CSF in proportion to their abundance in the peripheral circulation. Furthermore, the ready access of skin- and gut-homing CD4+ memory T cells to the CNS compartment via CSF has implications for the mechanisms of action of immunotherapeutic strategies, such as oral tolerance or therapeutic immunization, where immunogens are administered using an oral or subcutaneous route.

  15. Thermonuclear burn-up in deuterated methane $CD_4$

    CERN Document Server

    Frolov, Alexei M

    2010-01-01

    The thermonuclear burn-up of highly compressed deuterated methane CD$_4$ is considered in the spherical geometry. The minimal required values of the burn-up parameter $x = \\rho_0 \\cdot r_f$ are determined for various temperatures $T$ and densities $\\rho_0$. It is shown that thermonuclear burn-up in $CD_4$ becomes possible in practice if its initial density $\\rho_0$ exceeds $\\approx 5 \\cdot 10^3$ $g \\cdot cm^{-3}$. Burn-up in CD$_2$T$_2$ methane requires significantly ($\\approx$ 100 times) lower compressions. The developed approach can be used in order to compute the critical burn-up parameters in an arbitrary deuterium containing fuel.

  16. Lentiviral Nef-mediated CD4 and CD28 downmodulation

    OpenAIRE

    Heilmann, Jessica

    2014-01-01

    Different properties allow HIV-1 and SIV to establish a chronic disease, e.g. genome insertion into long living quiescent T cells, high genome mutations and evasion of the immune system. The lentiviral Nef protein undertakes important functions of evading the immune system. One of these functions is the downregulation of CD4 receptors from infected cell surfaces. Downregulation of the main entry receptor of HIV-1 prevents superinfection and related cell death, enhances release and infectivity...

  17. Human CD4+ T Cell Response to Human Herpesvirus 6

    OpenAIRE

    Nastke, Maria-D.; Becerra, Aniuska; Yin, Liusong; Dominguez-Amorocho, Omar; Gibson, Laura; Stern, Lawrence J.; Calvo-Calle, J. Mauricio

    2012-01-01

    Following primary infection, human herpesvirus 6 (HHV-6) establishes a persistent infection for life. HHV-6 reactivation has been associated with transplant rejection, delayed engraftment, encephalitis, muscular dystrophy, and drug-induced hypersensitivity syndrome. The poor understanding of the targets and outcome of the cellular immune response to HHV-6 makes it difficult to outline the role of HHV-6 in human disease. To fill in this gap, we characterized CD4 T cell responses to HHV-6 using...

  18. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Leslie R Cockerham

    Full Text Available The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1 in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4+ and CD8+ T cells expressing HLA-DR and the frequency of resting CD4+ T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies.

  19. Neoplasia hematodérmica CD4+ CD56+ en la infancia Hematodermic CD4+ CD56+ neoplasm in childhood

    Directory of Open Access Journals (Sweden)

    Erica A. Rojas Bilbao

    2008-04-01

    Full Text Available La neoplasia hematodérmica CD4+ CD56+ con fenotipo de célula dendrítica plasmocitoide es una rara y agresiva neoplasia recientemente reconocida por la WHO-EORTC classification. Afecta adultos de edad media y ancianos, siendo muy pocos los casos descriptos en niños. Presentamos el caso de una niña de 12 años con grave retraso mental, estigmas genéticos y múltiples lesiones cutáneas localizadas en miembros inferiores y superiores. Histológicamente se observó un infiltrado dérmico difuso de células pequeñas y medianas con expresión de CD4, CD56, CD43 y S100 así como de marcadores dendríticos plasmocitoides: CD 123 y BDCA-2 confirmados por citometría de flujo, sin compromiso de sangre periférica ni médula ósea. Cumpliendo dos semanas de tratamiento para leucemia linfoblástica aguda evolucionó con remisión clínica de las lesiones cutaneas.Hematodermic CD4+ CD56+ neoplasm with plasmacytoid dendritic cell phenotype is a rare and aggressive neoplasm recently recognized by the WHO-EORTC classification. It generally appears in elderly adults, exceptionally in childhood. We present a 12-year-old girl with severe mental retardation, genetic clinical features and multiple nodular cutaneous lesions on legs and arms. Histologically the nodules showed diffuse dermal infiltrate of medium and small cells and expression of CD4, CD56, CD43, S100 and plasmacytoid dendritic markers: CD123, BDCA-2 under flow cytometry study. Peripheral blood and bone marrow were not involved. Clinical remission of cutaneous lesions was observed after two weeks of acute lymphoblastic leukemia therapy.

  20. Utility of the point of care CD4 analyzer, PIMA, to enumerate CD4 counts in the field settings in India

    Directory of Open Access Journals (Sweden)

    Thakar Madhuri

    2012-09-01

    Full Text Available Abstract Background In resource limited settings non-availability of CD4 count facility at the site could adversely affect the ART roll out programme. Point of care CD4 enumerating equipments can make the CD4 count available at the site of care and improve the patients’ management considerably. This study is aimed at determining the utility of a Point of Care PIMA CD4 analyzer (Alere, Germany in the field settings in India. Method The blood samples were collected from 1790 participants at 21 ART centers from different parts of the country and tested using PIMA and the reference methods (FACSCalibur, FACSCount and CyFlow SL3. The paired finger prick and venous blood samples from 175 participants were tested by the PIMA CD4 Analyzer and then by FACSCalibur. Result The CD4 counts obtained by PIMA CD4 analyzer showed excellent correlation with the counts obtained by the reference methods; for venous blood the Pearson’s r was 0.921, p 500 cells/mm3, the differences in the median CD4 counts obtained by the reference method and the PIMA analyzer were not significant (P > 0.05 and the relative bias were low (−7 to 5.1%. The Intermachine comparison showed variation within the acceptable limit of%CV of 10%. Conclusion In the field settings, the POC PIMA CD4 analyzer gave CD4 counts comparable to the reference methods for all CD4 ranges. The POC equipment could identify the patients eligible for ART in 91% cases. Adequate training is necessary for finger prick sample collection for optimum results. Decentralization of CD4 testing by making the CD4 counts available at primary health centers, especially in remote areas with minimum or no infrastructure would reduce the missed visits and improve adherence of the patients.

  1. Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-Self CD4 Antibody Responses with Anti-Human Immunodeficiency Virus Activity

    Science.gov (United States)

    Watanabe, Mamoru; Boyson, Jonathan E.; Lord, Carol I.; Letvin, Norman L.

    1992-06-01

    In view of the efficiency with which human immunodeficiency virus replication can be blocked in vitro with anti-CD4 antibodies, the elicitation of an anti-CD4 antibody response through active immunization might represent a useful therapeutic strategy for AIDS. Here we demonstrate that immunization of chimpanzees with recombinant soluble human CD4 elicited an anti-CD4 antibody response. The elicited antibody bound self CD4 on digitonin-treated but not freshly isolated lymphocytes. Nevertheless, this antibody blocked human immunodeficiency virus replication in chimpanzee and human lymphocytes. These observations suggest that immunization with recombinant soluble CD4 from human immunodeficiency virus-infected humans may be feasible and therapeutically beneficial.

  2. CD4 estimating reagents in dry format are compatible with conventional flow cytometer; FACSCalibur for estimation of absolute CD4 count & percentages

    OpenAIRE

    Madhuri Thakar; Bharati Mahajan; Trupti Joshi; Suvarna Sane; Ramesh Paranjape

    2013-01-01

    Background & objectives: Reliable CD4 counts are important for successful implementation of antiretroviral treatment (ART). Availability of dry CD4 reagents can eliminate cold chain requirement reducing shipment and storage cost. An attempt was made in this study to validate the ReaPan and Rea T Count dry reagents developed by ReaMetrix against the original BD Biosciences liquid reagents. Method: Absolute counts and percentages of CD4, CD8 and CD3 + T cells obtained in 100 HIV infected ind...

  3. Gut Mucosal FOXP3+ Regulatory CD4+ T Cells and Nonregulatory CD4+ T Cells Are Differentially Affected by Simian Immunodeficiency Virus Infection in Rhesus Macaques▿

    OpenAIRE

    Allers, Kristina; Loddenkemper, Christoph; Hofmann, Jörg; Unbehaun, Anett; Kunkel, Désirée; Moos, Verena; Kaup, Franz-Josef; Stahl-Hennig, Christiane; Sauermann, Ulrike; Epple, Hans-Jörg; Schneider, Thomas

    2010-01-01

    The gastrointestinal tract represents a major site for human and simian immunodeficiency virus (HIV and SIV) replication and CD4+ T-cell depletion. Despite severe depletion of mucosal CD4+ T cells, FOXP3+ regulatory CD4+ T cells (Treg) are highly increased in the gut mucosa of chronically HIV-infected individuals and may contribute to HIV pathogenesis, either by their immunosuppressive function or as a significant target cell population for virus production. Little is known about the suscepti...

  4. Depletion of the surface CD4 molecule by the envelope protein of human immunodeficiency virus expressed in a human CD4+ monocytoid cell line

    International Nuclear Information System (INIS)

    A CD4+ human monocytoid cell line, U937, was transfected with a constructed plasmid which has the envelope gene of human immunodeficiency virus under the transcriptional control of the human metallothionein IIA promoter and was cloned thereafter. These cloned cell lines (EH and EL cells) expressed the viral gp160 in the cytoplasm. The expression of surface CD4 antigen examined by Leu3a and OKT4 monoclonal antibodies, however, disappeared completely in EH cells, which produce a larger amount of gp160, while diminishing only partly in EL cells, which produce a smaller amount of gp160. These results indicate that the level of expression of surface CD4 antigen correlates inversely with the amount of intracellular gp160. Moreover, immunoprecipitation studies using lysate from EH cells showed that OKT4 monoclonal antibody precipitated a significant number of CD4 molecules even after surface CD4 disappeared. However, Leu3a monoclonal antibody, which recognizes the binding site for envelope protein, could not precipitate any CD4 molecules in the same cell lysate. Taken together, these results suggested that CD4 molecules are still synthesized normally after the augmented production of gp160 in the cells but form a complex with the envelope protein in the cytoplasm and become unable to be transported to the cell surface, resulting in the observed depletion of surface CD4 antigen. This mechanism may explain the decrease or absence of surface CD4 antigens in human lymphocytes infected with human immunodeficiency virus

  5. Stabilization of HIV-1 gp120-CD4 Receptor Complex through Targeted Interchain Disulfide Exchange*

    OpenAIRE

    Cerutti, Nichole; Mendelow, Barry V.; Napier, Grant B.; Papathanasopoulos, Maria A.; Killick, Mark; Khati, Makobetsa; Stevens, Wendy; Capovilla, Alexio

    2010-01-01

    HIV-1 enters cells via interaction between the trimeric envelope (Env) glycoprotein gp120/gp41 and the host cell surface receptor molecule CD4. The requirement of CD4 for viral entry has rationalized the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. In this study, we describe a novel recombinant CD4 protein designed to bind gp120 through a targeted disulfide-exchange mechanism. According to structural models of the gp120...

  6. Neoplasia hematodérmica CD4+ CD56+ en la infancia Hematodermic CD4+ CD56+ neoplasm in childhood

    OpenAIRE

    Erica A. Rojas Bilbao; Ana María Chirife; Darío Llorio; Lliliana B. Giménez; Lina Marino; Diego A. Rosso

    2008-01-01

    La neoplasia hematodérmica CD4+ CD56+ con fenotipo de célula dendrítica plasmocitoide es una rara y agresiva neoplasia recientemente reconocida por la WHO-EORTC classification. Afecta adultos de edad media y ancianos, siendo muy pocos los casos descriptos en niños. Presentamos el caso de una niña de 12 años con grave retraso mental, estigmas genéticos y múltiples lesiones cutáneas localizadas en miembros inferiores y superiores. Histológicamente se observó un infiltrado dérmico difuso de célu...

  7. CTLA-4 is Required by CD4+CD25+ Treg to Control CD4+ T Cell Lymphopenia-Induced Proliferation

    OpenAIRE

    Sojka, Dorothy K.; Hughson, Angela; Fowell, Deborah J.

    2009-01-01

    CTLA-4 is constitutively expressed by CD4+CD25+Foxp3+ regulatory T cells (Treg) but its precise role in Treg function is not clear. Although blockade of CTLA-4 interferes with Treg function, studies using CTLA-4 deficient Treg have failed to reveal an essential requirement for CTLA-4 in Treg suppression in vivo. Conditional deletion of CTLA-4 in Foxp3+ T cells disrupts immune homeostasis in vivo but the immune processes disrupted by CTLA-4 deletion have not been determined. We demonstrate tha...

  8. Spleen-resident CD4+ and CD4- CD8α- dendritic cell subsets differ in their ability to prime invariant natural killer T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Emilie Bialecki

    Full Text Available One important function of conventional dendritic cells (cDC is their high capacity to capture, process and present Ag to T lymphocytes. Mouse splenic cDC subtypes, including CD8α(+ and CD8α(- cDC, are not identical in their Ag presenting and T cell priming functions. Surprisingly, few studies have reported functional differences between CD4(- and CD4(+ CD8α(- cDC subsets. We show that, when loaded in vitro with OVA peptide or whole protein, and in steady-state conditions, splenic CD4(- and CD4(+ cDC are equivalent in their capacity to prime and direct CD4(+ and CD8(+ T cell differentiation. In contrast, in response to α-galactosylceramide (α-GalCer, CD4(- and CD4(+ cDC differentially activate invariant Natural Killer T (iNKT cells, a population of lipid-reactive non-conventional T lymphocytes. Both cDC subsets equally take up α-GalCer in vitro and in vivo to stimulate the iNKT hybridoma DN32.D3, the activation of which depends solely on TCR triggering. On the other hand, and relative to their CD4(+ counterparts, CD4(- cDC more efficiently stimulate primary iNKT cells, a phenomenon likely due to differential production of co-factors (including IL-12 by cDC. Our data reveal a novel functional difference between splenic CD4(+ and CD4(- cDC subsets that may be important in immune responses.

  9. Elicitation of neutralizing antibodies directed against CD4-induced epitope(s using a CD4 mimetic cross-linked to a HIV-1 envelope glycoprotein.

    Directory of Open Access Journals (Sweden)

    Antu K Dey

    Full Text Available The identification of HIV-1 envelope glycoprotein (Env structures that can generate broadly neutralizing antibodies (BNAbs is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4 receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i epitope(s known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH, was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140 using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1 complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2(7312/V434M and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s. These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s here, and its potential role in vaccine application.

  10. Enteric parasitic infections in HIV-infected patients with low CD4 counts in Toto, Nigeria

    International Nuclear Information System (INIS)

    Objectives: Enteric parasites are a major cause of diarrhoea in HIV/AIDS patients with low CD4 counts. Parasitic infections in HIV-infected individuals can reduce their quality of life and life span, especially those who are severely immunosuppressed with a CD4 T-lymphocyte count 0.05). Conclusions: Low CD4 counts in HIV-infected patients can lead to enteric infections. This information strengthens the importance of monitoring CD4 counts and intestinal parasites. Routine CD4 testing will greatly improve the prognosis of HIV positive patients. (author)

  11. Auditing National HIV Guidelines and Policies: The United Kingdom CD4 Surveillance Scheme

    OpenAIRE

    Brown, Alison E; Kall, Meaghan M; Smith, Ruth D; Yin, Zheng; Hunter, Alan; Valerie C Delpech

    2012-01-01

    The United Kingdom’s CD4 surveillance scheme monitors CD4 cell counts among HIV patients and is a national resource for HIV surveillance. It has driven public health policy and allowed auditing of national HIV testing, treatment and care guidelines. We demonstrate its utility through four example outputs: median CD4 count at HIV diagnosis; late HIV diagnosis and short-term mortality; the timing of first CD4 count to indicate entry into HIV care; and the proportion of patients with CD4 counts

  12. Computed CD4 percentage as a low-cost method for determining pediatric antiretroviral treatment eligibility

    Directory of Open Access Journals (Sweden)

    Colebunders Robert

    2008-03-01

    Full Text Available Abstract Background The performance of the WHO recommendations for pediatric antiretroviral treatment (ART in resource poor settings is insufficiently documented in routine care. Methods We compared clinical and immunological criteria in 366 children aged 0 to 12 years in Kinshasa and evaluated a simple computation to estimate CD4 percent, based on CD4 count, total white blood cell count and percentage lymphocytes. Kappa (κ statistic was used to evaluate eligibility criteria and linear regression to determine trends of CD4 percent, count and total lymphocyte count (TLC. Results Agreement between clinical and immunological eligibility criteria was poor (κ = 0.26. One third of children clinically eligible for ART were ineligible using immunological criteria; one third of children immunologically eligible were ineligible using clinical criteria. Among children presenting in WHO stage I or II, 54 (32% were eligible according to immunological criteria. Agreement with CD4 percent was poor for TLC (κ = 0.04, fair for total CD4 count (κ = 0.39 and substantial for CD4 percent computational estimate (κ = 0.71. Among 5 to 12 years old children, total CD4 count was higher in younger age groups (-32 cells/mm3 per year older, CD4 percent was similar across age groups. Conclusion Age-specific thresholds for CD4 percent optimally determine pediatric ART eligibility. The use of CD4 percent computational estimate may increase ART access in settings with limited access to CD4 percent assays.

  13. CD4 T-cell enumeration in a field setting: evaluation of CyFlow counter using the CD4 easy count kit-dry and Pima CD4 systems.

    Directory of Open Access Journals (Sweden)

    Djibril Wade

    Full Text Available BACKGROUND: Flow Cytometry (FCM is still considered to be the method of choice for accurate CD4 enumeration. However, the use of FCM in developing countries is problematic due to their cost and complexity. Lower-cost technologies have been introduced. We evaluated CyFlow Counter together with its lyophilized reagents, and Pima CD4 in high-temperature area, using FACSCount as reference. MATERIALS AND METHODS: Whole blood samples were consecutively collected by venipuncture from 111 HIV+ patients and 17 HIV-negative donors. CD4 T-cell enumeration was performed on CyFlow Counter, Pima CD4 and FACSCount. RESULTS: CyFlow Counter and Pima CD4 systems showed good correlation with FACSCount (slope of 0.82 and 0.90, and concordance ρc of 0.94 and 0.98, respectively. CyFlow Counter showed absolute or relative biases (LOA of -63 cells/mm(3 (-245 to 120 or -9.8% (-38.1 to 18.4 respectively, and Pima CD4 showed biases (LOA of -30 cells/mm(3 (-160 to 101 or -3.5% (-41.0 to 33.9%. CyFlow Counter and Pima CD4 showed respectively 106.7% and 105.9% of similarity with FACSCount. According to WHO-2010 ART initiation threshold of 350 cells/mm(3, CyFlow Counter and Pima CD4 showed respectively sensibility of 100% and 97%, and specificity of 91% and 93%. CyFlow Counter and Pima CD4 were strongly correlated (slope of 1.09 and ρc of 0.95. These alternative systems showed good agreement with bias of 33 cells/mm(3 (-132 to 203 or 6.3% (-31.2 to 43.8, and similarity of 104.3%. CONCLUSION: CyFlow Counter using CD4 easy count kit-dry and Pima CD4 systems can accurately provide CD4 T-cell counts with acceptable agreement to those of FACSCount.

  14. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

    International Nuclear Information System (INIS)

    Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg). C57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry. Whole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice. The response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease

  15. Dietary fish oil and DHA down-regulate antigen-activated CD4+ T-cells while promoting the formation of liquid-ordered mesodomains.

    Science.gov (United States)

    Kim, Wooki; Barhoumi, Rola; McMurray, David N; Chapkin, Robert S

    2014-01-28

    We have demonstrated previously that n-3 PUFA endogenously produced by fat-1 transgenic mice regulate CD4+ T-cell function by affecting the formation of lipid rafts, liquid-ordered mesodomains in the plasma membrane. In the present study, we tested the effects of dietary sources of n-3 PUFA, i.e. fish oil (FO) or purified DHA, when compared with an n-6 PUFA-enriched maize oil control diet in DO11.10 T-cell receptor transgenic mice. Dietary n-3 PUFA were enriched in CD4+ T-cells, resulting in the increase of the n-3:n-6 ratio. Following antigen-specific CD4+ T-cell activation by B-lymphoma cells pulsed with the ovalbumin 323-339 peptide, the formation of liquid-ordered mesodomains at the immunological synapse relative to the whole CD4+ T-cell, as assessed by Laurdan labelling, was increased (P< 0·05) in the FO-fed group. The FO diet also suppressed (P< 0·05) the co-localisation of PKCθ with ganglioside GM1 (monosialotetrahexosylganglioside), a marker for lipid rafts, which is consistent with previous observations. In contrast, the DHA diet down-regulated (P< 0·05) PKCθ signalling by moderately affecting the membrane liquid order at the immunological synapse, suggesting the potential contribution of the other major n-3 PUFA components of FO, including EPA. PMID:23962659

  16. Stabilization of HIV-1 gp120-CD4 receptor complex through targeted interchain disulfide exchange.

    Science.gov (United States)

    Cerutti, Nichole; Mendelow, Barry V; Napier, Grant B; Papathanasopoulos, Maria A; Killick, Mark; Khati, Makobetsa; Stevens, Wendy; Capovilla, Alexio

    2010-08-13

    HIV-1 enters cells via interaction between the trimeric envelope (Env) glycoprotein gp120/gp41 and the host cell surface receptor molecule CD4. The requirement of CD4 for viral entry has rationalized the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. In this study, we describe a novel recombinant CD4 protein designed to bind gp120 through a targeted disulfide-exchange mechanism. According to structural models of the gp120-CD4 receptor complex, substitution of Ser(60) on the CD4 domain 1 alpha-helix with Cys positions a thiol in proximity of the gp120 V1/V2 loop disulfide (Cys(126)-Cys(196)), satisfying the stereochemical and geometric conditions for redox exchange between CD4 Cys(60) and gp120 Cys(126), and the consequent formation of an interchain disulfide bond. In this study, we provide experimental evidence for this effect by describing the expression, purification, refolding, receptor binding and antiviral activity analysis of a recombinant two-domain CD4 variant containing the S60C mutation (2dCD4-S60C). We show that 2dCD4-S60C binds HIV-1 gp120 with a significantly higher affinity than wild-type protein under conditions that facilitate disulfide exchange and that this translates into a corresponding increase in the efficacy of CD4-mediated viral entry inhibition. We propose that targeted redox exchange between conserved gp120 disulfides and nucleophilic moieties positioned strategically on CD4 (or CD4-like scaffolds) conceptualizes a new strategy in the development of high affinity HIV-1 Env ligands, with important implications for therapy and vaccine development. More generally, this chalcogen substitution approach provides a general means of stabilizing receptor-ligand complexes where the structural and biophysical conditions for disulfide exchange are satisfied. PMID:20538591

  17. Stabilization of HIV-1 gp120-CD4 Receptor Complex through Targeted Interchain Disulfide Exchange*

    Science.gov (United States)

    Cerutti, Nichole; Mendelow, Barry V.; Napier, Grant B.; Papathanasopoulos, Maria A.; Killick, Mark; Khati, Makobetsa; Stevens, Wendy; Capovilla, Alexio

    2010-01-01

    HIV-1 enters cells via interaction between the trimeric envelope (Env) glycoprotein gp120/gp41 and the host cell surface receptor molecule CD4. The requirement of CD4 for viral entry has rationalized the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. In this study, we describe a novel recombinant CD4 protein designed to bind gp120 through a targeted disulfide-exchange mechanism. According to structural models of the gp120-CD4 receptor complex, substitution of Ser60 on the CD4 domain 1 α-helix with Cys positions a thiol in proximity of the gp120 V1/V2 loop disulfide (Cys126–Cys196), satisfying the stereochemical and geometric conditions for redox exchange between CD4 Cys60 and gp120 Cys126, and the consequent formation of an interchain disulfide bond. In this study, we provide experimental evidence for this effect by describing the expression, purification, refolding, receptor binding and antiviral activity analysis of a recombinant two-domain CD4 variant containing the S60C mutation (2dCD4-S60C). We show that 2dCD4-S60C binds HIV-1 gp120 with a significantly higher affinity than wild-type protein under conditions that facilitate disulfide exchange and that this translates into a corresponding increase in the efficacy of CD4-mediated viral entry inhibition. We propose that targeted redox exchange between conserved gp120 disulfides and nucleophilic moieties positioned strategically on CD4 (or CD4-like scaffolds) conceptualizes a new strategy in the development of high affinity HIV-1 Env ligands, with important implications for therapy and vaccine development. More generally, this chalcogen substitution approach provides a general means of stabilizing receptor-ligand complexes where the structural and biophysical conditions for disulfide exchange are satisfied. PMID:20538591

  18. HIV/AIDS合并妊娠的CD4+T淋巴细胞临床观察%HIVIAIDS in pregnancy the CD4+lymphocytes in clinical observation

    Institute of Scientific and Technical Information of China (English)

    郭晓峰; 唐小平; 蔡卫平; 何浩岚

    2009-01-01

    目的 探讨HIV/AIDS合并妊娠规范使用抗病毒药物后CD4+T淋巴细胞的变化规律.方法 回顾性分析36例HIV/AIDS孕产妇CD4+T淋巴细胞计数及CD4+/CD8+比值变化,其中具有孕期、产后(3个月内)连续的CD4+、CD8+T淋巴细胞计数及CD4+/CD8+比值资料的有1 7例.结果 36例患者CD4+计数最小值80个/uL,最大值743个/uL,中位数367个/uL.其中17例患者孕期CD4+计数最小值80个/uL,最大值588个/uL,中位教313个/uL;产后(3个月内)CD4+计数最小值139个/uL,最大值737个/uL,中位数391个/uL;孕期CD4+/CD8+比值最低0.13,最高0.89,中位数0.41,产后CD4+/CD8+比值最低0.17,最高1.2,中位数0.51. 结论 本组17名HIV/AIDS孕产妇孕期、产后CD4+T淋巴细胞计数及CD4+/CD8+比值变化为产后有逐渐上升的趋势,但x 2检验差异无统计学意义.

  19. Increased cytotoxicity of CD4+ invariant NKT cells against CD4+CD25hiCD127lo/− regulatory T cells in allergic asthma

    OpenAIRE

    Nguyen, Khoa D.; Vanichsarn, Chris; Nadeau, Kari C.

    2008-01-01

    CD4+CD25hiCD127lo/− regulatory T cells (Treg) have been implicated in the resolution of asthma-associated inflammation while the opposite role of CD4+ invariant NKT (iNKT) cells has been the subject of recent investigations. Studies here focused on mechanisms of interaction between CD4+ iNKT cells and Treg to further explore their roles in allergic asthma (AA). Flow cytometry analysis revealed a significant increase in the expression of the natural cytotoxicity receptors NKp30 and NKp46 by CD...

  20. Decreased percentage of CD4+Foxp3+TGF-β+ and increased percentage of CD4+IL-17+ cells in bronchoalveolar lavage of asthmatics

    OpenAIRE

    Barczyk, Adam; Pierzchala, Wladyslaw; Caramori, Gaetano; Wiaderkiewicz, Ryszard; Kaminski, Marcin; Barnes, Peter J; Adcock, Ian M.

    2014-01-01

    Background Asthma is a chronic inflammatory disorder of the airways with the proven role of Th2 cells in its pathogenesis. The role and characteristic of different subsets of CD4+ cells is much less known. Aim The aim of the study was to analyze the incidence of different subsets of CD4+ T cells, in particular different subsets of CD4+ cells with the co-expression of different cytokines. Methods Twenty five stable asthmatic and twelve age-matched control subjects were recruited to the study. ...

  1. SMARThivCD4mos: A complexity-free and cost effective model technology for monitoring HIV patients CD4 number in resource-poor settings

    OpenAIRE

    Yari, Aboubakar; Passo, Frederic S; Yari, Venus; Sanni, Ousmane; Yari, Myra; Dovenou, Mathieu Z; Traore, Rachide; Hounyet, Jean-Pierre

    2008-01-01

    We design a “simple” and “low cost” model technology for monitoring HIV patients CD4 number in resource-poor settings: SMARThivCD4mos. Cost and complexity are the major challenges to the developing world in transferring and implementing HIV surveillance technologies. We previously proposed a “three tests” combo kit model for improving HIV patients monitoring standards in resource-poor settings. From the pool of recommended alternative CD4 counting technologies, our “three tests” combo kit mod...

  2. The T-cell accessory molecule CD4 recognizes a monomorphic determinant on isolated Ia

    DEFF Research Database (Denmark)

    Gay, D; Buus, S; Pasternak, J;

    1988-01-01

    The membrane protein CD4 is commonly found on mature T cells specific for antigen in association with class II major histocompatibility complex (MHC; Ia) proteins. This correlation has led to the suggestion that CD4 binds to a monomorphic region of the Ia molecule on the antigen-presenting cell...... proteins into a planar membrane system, we show that different Ia molecules can greatly enhance the ability of a CD4+ but not a CD4- variant of this class I-restricted T hybrid to respond to isolated class I molecules. T-cell responses can be strongly augmented by the concurrent expression of CD4 on the T...... cell and any of four different Ia proteins on planar membranes, thus supporting the idea that CD4 binds to a monomorphic region of the Ia molecule and increases the avidity with which the T cell can interact with its target....

  3. MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV(162P3 in cynomolgus macaques.

    Directory of Open Access Journals (Sweden)

    Nathalie Dereuddre-Bosquet

    Full Text Available In complement to an effective vaccine, development of potent anti-HIV microbicides remains an important priority. We have previously shown that the miniCD4 M48U1, a functional mimetic of sCD4 presented on a 27 amino-acid stable scaffold, inhibits a broad range of HIV-1 isolates at sub-nanomolar concentrations in cellular models. Here, we report that M48U1 inhibits efficiently HIV-1(Ba-L in human mucosal explants of cervical and colorectal tissues. In vivo efficacy of M48U1 was evaluated in nonhuman primate (NHP model of mucosal challenge with SHIV(162P3 after assessing pharmacokinetics and pharmacodynamics of a miniCD4 gel formulation in sexually matured female cynomolgus macaques. Among 12 females, half were treated with hydroxyethylcellulose-based gel (control, the other half received the same gel containing 3 mg/g of M48U1, one hour before vaginal route challenge with 10 AID(50 of SHIV(162P3. All control animals were infected with a peak plasma viral load of 10(5-10(6 viral RNA (vRNA copies per mL. In animals treated with miniCD4, 5 out of 6 were fully protected from acquisition of infection, as assessed by qRT-PCR for vRNA detection in plasma, qPCR for viral DNA detection in PBMC and lymph node cells. The only infected animal in this group had a delayed peak of viremia of one week. These results demonstrate that M48U1 miniCD4 acts in vivo as a potent entry inhibitor, which may be considered in microbicide developments.

  4. CORRELATION BETWEEN CLINICAL PROFILE, CD 4 COUNT AND TOTAL LYMPHOCYTE COUNT IN HIV INFECTED PERSONS

    OpenAIRE

    Keshava; Manjunath

    2014-01-01

    BACKGROUND & OBJECTIVES: HIV infection can be monitored by laboratory and clinical markers of disease progression. In the absence of CD 4 count , the use of Total Lymphocyte Count has been advocated to predict CD 4 count and to stage HIV disease. This study was undertaken to show whether the TLC accurately predicts a low CD 4 count in HIV infected persons and its clinical correlation. METHODOLOGY: The data for the study was collected from HIV positive inpatien...

  5. Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells MDSC and CD4+ T cells

    OpenAIRE

    Nagaraj, Srinivas; Gabrilovich, Dmitry I.

    2012-01-01

    Myeloid derived Suppressor Cells play a critical role in T cell suppression in cancer. Here, we discuss the mechanisms of how MDSC suppress CD4+ or CD8+ T cells in an antigen dependent or non-dependent manner.

  6. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells.

    Science.gov (United States)

    Makita, Shin; Kanai, Takanori; Oshima, Shigeru; Uraushihara, Koji; Totsuka, Teruji; Sawada, Taisuke; Nakamura, Tetsuya; Koganei, Kazutaka; Fukushima, Tsuneo; Watanabe, Mamoru

    2004-09-01

    It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4(+)CD25(bright) T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4(+) T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4(+)CD25(-) T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4(+)CD25(+) T cells, however, cells expressing CD25 at high levels (CD4(+)CD25(bright)) suppressed the proliferation and various cytokine productions of CD4(+)CD25(-) T cells. LP CD4(+)CD25(bright) T cells by themselves produced fewer amounts of IL-2, IFN-gamma, and IL-10. Interestingly, LP CD4(+)CD25(bright) T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4(+)CD25(bright) T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis. PMID:15322172

  7. Combination effect on HIV infection in vitro of soluble CD4 and HIV-neutralizing antibodies

    DEFF Research Database (Denmark)

    Hansen, J E; Sørensen, A M; Olofsson, S; Osinaga, E; Roseto, A

    In combination with HIV gp120 V3-loop antibody, two carbohydrate specific neutralizing antibodies (83D4 and 2G12) had a synergistic neutralizing effect on HIV infection. However, sCD4 and an antibody which blocks gp 120/CD4 binding (1B1) both displayed antagonism.......In combination with HIV gp120 V3-loop antibody, two carbohydrate specific neutralizing antibodies (83D4 and 2G12) had a synergistic neutralizing effect on HIV infection. However, sCD4 and an antibody which blocks gp 120/CD4 binding (1B1) both displayed antagonism....

  8. Multifunctional CD4 T Cell Responses in Patients with Active Tuberculosis

    OpenAIRE

    Qiu, Zhengang; Zhang, Mingxia; Zhu, Yuzhen; Zheng, Feiqun; Lu, Puxuan; Liu, Haiying; Michael W Graner; Zhou, Boping; Chen, Xinchun

    2012-01-01

    The roles of multifunctional CD4 T cells in human tuberculosis are not well defined. In this study, we found that patients with tuberculosis had decreased PMA/ionomycin stimulated multifunctional CD4 T cells, and increased Mycobacterium tuberculosis antigen-specific multifunctional CD4 T cells, when compared to individuals with latent tuberculosis infection and healthy controls. PMA/ionomycin stimulated IFN-γ+IL-2+TNF-α+ CD4 T cell responses were decreased in patients with smear-positive tube...

  9. Regulatory function of cytomegalovirus-specific CD4+CD27-CD28- T cells

    International Nuclear Information System (INIS)

    CMV infection is characterized by high of frequencies of CD27-CD28- T cells. Here we demonstrate that CMV-specific CD4+CD27-CD28- cells are regulatory T cells (TR). CD4+CD27-CD28- cells sorted from CMV-stimulated PBMC of CMV-seropositive donors inhibited de novo CMV-specific proliferation of autologous PBMC in a dose-dependent fashion. Compared with the entire CMV-stimulated CD4+ T-cell population, higher proportions of CD4+CD27-CD28- TR expressed FoxP3, TGFβ, granzyme B, perforin, GITR and PD-1, lower proportions expressed CD127 and PD1-L and similar proportions expressed CD25, CTLA4, Fas-L and GITR-L. CMV-CD4+CD27-CD28- TR expanded in response to IL-2, but not to CMV antigenic restimulation. The anti-proliferative effect of CMV-CD4+CD27-CD28- TR significantly decreased after granzyme B or TGFβ inhibition. The CMV-CD4+CD27-CD28- TR of HIV-infected and uninfected donors had similar phenotypes and anti-proliferative potency, but HIV-infected individuals had higher proportions of CMV-CD4+CD27-CD28- TR. The CMV-CD4+CD27-CD28- TR may contribute to the downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.

  10. Clinical Evaluation of the BD FACSPresto™ Near-Patient CD4 Counter in Kenya

    Science.gov (United States)

    Angira, Francis; Akoth, Benta; Omolo, Paul; Opollo, Valarie; Bornheimer, Scott; Judge, Kevin; Tilahun, Henok; Lu, Beverly; Omana-Zapata, Imelda; Zeh, Clement

    2016-01-01

    Background The BD FACSPresto™ Near-Patient CD4 Counter was developed to expand HIV/AIDS management in resource-limited settings. It measures absolute CD4 counts (AbsCD4), percent CD4 (%CD4), and hemoglobin (Hb) from a single drop of capillary or venous blood in approximately 23 minutes, with throughput of 10 samples per hour. We assessed the performance of the BD FACSPresto system, evaluating accuracy, stability, linearity, precision, and reference intervals using capillary and venous blood at KEMRI/CDC HIV-research laboratory, Kisumu, Kenya, and precision and linearity at BD Biosciences, California, USA. Methods For accuracy, venous samples were tested using the BD FACSCalibur™ instrument with BD Tritest™ CD3/CD4/CD45 reagent, BD Trucount™ tubes, and BD Multiset™ software for AbsCD4 and %CD4, and the Sysmex™ KX-21N for Hb. Stability studies evaluated duration of staining (18–120-minute incubation), and effects of venous blood storage <6–24 hours post-draw. A normal cohort was tested for reference intervals. Precision covered multiple days, operators, and instruments. Linearity required mixing two pools of samples, to obtain evenly spaced concentrations for AbsCD4, total lymphocytes, and Hb. Results AbsCD4 and %CD4 venous/capillary (N = 189/ N = 162) accuracy results gave Deming regression slopes within 0.97–1.03 and R2 ≥0.96. For Hb, Deming regression results were R2 ≥0.94 and slope ≥0.94 for both venous and capillary samples. Stability varied within 10% 2 hours after staining and for venous blood stored less than 24 hours. Reference intervals results showed that gender—but not age—differences were statistically significant (p<0.05). Precision results had <3.5% coefficient of variation for AbsCD4, %CD4, and Hb, except for low AbsCD4 samples (<6.8%). Linearity was 42–4,897 cells/μL for AbsCD4, 182–11,704 cells/μL for total lymphocytes, and 2–24 g/dL for Hb. Conclusions The BD FACSPresto system provides accurate, precise clinical

  11. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    Science.gov (United States)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-02-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

  12. Exploration of the Partial Different Roles of CD4 + CD25 + Tregs and CD4 + CD25HighTregs in Sero-resistance Syphilitic Patients%梅毒血清固定患者CD4+CD25+Treg细胞和CD4+CD25High Treg细胞功能的差异探讨

    Institute of Scientific and Technical Information of China (English)

    张明海; 赵建斌

    2013-01-01

    目的 探讨梅毒血清固定患者外周血CD4+ CD25+ Treg细胞和CD4+ CD25HighTreg细胞功能是否发生变化.方法 采用流式细胞术(FCM)检测28例梅毒血清固定患者和28例梅毒转阴患者外周血CD4+CD25+ Treg细胞和CD4+ CD25High Treg细胞中FOXP3和CTLA-4的水平;采用免疫磁珠细胞分选技术(MACS)和Realtime-PCR技术检测CD4+ CD25+ Treg细胞的FOXP3和CTLA-4mRNA水平.结果 梅毒血清固定组外周血CD4+ CD25+Treg细胞功能增强,而梅毒血清转阴组外周血CD4+ CD25HighTreg细胞功能稳定.结论 CD4+CD25+Treg和CD4+ CD25HighTreg细胞在梅毒血清固定形成中作用的方式或途径存在部分差异.

  13. Enhanced HIV-1 neutralization by a CD4-VH3-IgG1 fusion protein

    International Nuclear Information System (INIS)

    HIV-1 gp120 is an alleged B cell superantigen, binding certain VH3+ human antibodies. We reasoned that a CD4-VH3 fusion protein could possess higher affinity for gp120 and improved HIV-1 inhibitory capacity. To test this we produced several human IgG1 immunoligands harboring VH3. Unlike VH3-IgG1 or VH3-CD4-IgG1, CD4-VH3-IgG1 bound gp120 considerably stronger than CD4-IgG1. CD4-VH3-IgG1 exhibited ∼1.5-2.5-fold increase in neutralization of two T-cell laboratory-adapted strains when compared to CD4-IgG1. CD4-VH3-IgG1 improved neutralization of 7/10 clade B primary isolates or pseudoviruses, exceeding 20-fold for JR-FL and 13-fold for Ba-L. It enhanced neutralization of 4/8 clade C viruses, and had negligible effect on 1/4 clade A pseudoviruses. We attribute this improvement to possible pairing of VH3 with CD4 D1 and stabilization of an Ig Fv-like structure, rather than to superantigen interactions. These novel findings support the current notion that CD4 fusion proteins can act as better HIV-1 entry inhibitors with potential clinical implications.

  14. High-throughput sequencing reveals restricted TCR Vβ usage and public TCRβ clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes.

    Science.gov (United States)

    Marrero, Idania; Aguilera, Carlos; Hamm, David E; Quinn, Anthony; Kumar, Vipin

    2016-06-01

    Islet-reactive memory CD4(+) T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCRβ repertoire of memory CD4(+) T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCRβ repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCRβ overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCRβ clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (Vβ8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR Vβ8.2 chain led to protection from diabetes, suggesting a critical role for Vβ8.2(+) CD4(+) memory T cells in T1D. These results suggest that memory CD4(+) T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D. PMID:27161799

  15. Palmitic acid analogs exhibit nanomolar binding affinity for the HIV-1 CD4 receptor and nanomolar inhibition of gp120-to-CD4 fusion.

    Directory of Open Access Journals (Sweden)

    Elena E Paskaleva

    Full Text Available BACKGROUND: We recently reported that palmitic acid (PA is a novel and efficient CD4 fusion inhibitor to HIV-1 entry and infection. In the present report, based on in silico modeling of the novel CD4 pocket that binds PA, we describe discovery of highly potent PA analogs with increased CD4 receptor binding affinities (K(d and gp120-to-CD4 inhibition constants (K(i. The PA analogs were selected to satisfy Lipinski's rule of drug-likeness, increased solubility, and to avoid potential cytotoxicity. PRINCIPAL FINDINGS: PA analog 2-bromopalmitate (2-BP was most efficacious with K(d approximately 74 nM and K(i approximately 122 nM, ascorbyl palmitate (6-AP exhibited slightly higher K(d approximately 140 nM and K(i approximately 354 nM, and sucrose palmitate (SP was least efficacious binding to CD4 with K(d approximately 364 nM and inhibiting gp120-to-CD4 binding with K(i approximately 1486 nM. Importantly, PA and its analogs specifically bound to the CD4 receptor with the one to one stoichiometry. SIGNIFICANCE: Considering observed differences between K(i and K(d values indicates clear and rational direction for improving inhibition efficacy to HIV-1 entry and infection. Taken together this report introduces a novel class of natural small molecules fusion inhibitors with nanomolar efficacy of CD4 receptor binding and inhibition of HIV-1 entry.

  16. Cervical Cancer

    Science.gov (United States)

    ... the place where a baby grows during pregnancy. Cervical cancer is caused by a virus called HPV. The ... for a long time, or have HIV infection. Cervical cancer may not cause any symptoms at first. Later, ...

  17. Cervical Cancer

    Centers for Disease Control (CDC) Podcasts

    2007-03-06

    Did you know that cervical cancer rates differ by race/ethnicity and region? Or that cervical cancer can usually be prevented if precancerous cervical lesions are found by a Pap test and treated? Find out how getting regular Pap tests can save a woman's life.  Created: 3/6/2007 by National Breast and Cervical Cancer Early Detection Program.   Date Released: 4/25/2007.

  18. Auditing national HIV guidelines and policies: The United Kingdom CD4 Surveillance Scheme.

    Science.gov (United States)

    Brown, Alison E; Kall, Meaghan M; Smith, Ruth D; Yin, Zheng; Hunter, Alan; Hunter, Alan; Delpech, Valerie C

    2012-01-01

    The United Kingdom's CD4 surveillance scheme monitors CD4 cell counts among HIV patients and is a national resource for HIV surveillance. It has driven public health policy and allowed auditing of national HIV testing, treatment and care guidelines. WE DEMONSTRATE ITS UTILITY THROUGH FOUR EXAMPLE OUTPUTS: median CD4 count at HIV diagnosis; late HIV diagnosis and short-term mortality; the timing of first CD4 count to indicate entry into HIV care; and the proportion of patients with CD4 counts <350 cells/mm3 receiving anti-retroviral therapy (ARV). In 2009, 95% (61,502/64,420) of adults living with diagnosed HIV infection had CD4 counts available. The median CD4 count at diagnosis increased from 276 to 335 cells/mm3 between 2000 and 2009, indicating modest improvements in HIV testing. In 2009, 52% of patients were diagnosed at a late stage of HIV infection (CD4 <350 cells/mm(3)); these individuals had a ten-fold risk of dying within a year of their diagnosis compared to those diagnosed promptly. In 2008, the national target of performing a CD4 count within 14 days of diagnosis was met for 61% of patients. National treatment guidelines have largely been met with 83% patients with CD4 <350 cells/mm(3) receiving ARV. The monitoring of CD4 counts is critical to HIV surveillance in the United Kingdom enabling the close monitoring of efforts to reduce morbidity and mortality associated with late diagnosis and underpins the auditing of policies and guidelines. These routine surveillance outputs can be generated at national and local levels to drive and monitor public health policy and prevention efforts. PMID:23049663

  19. Characterization of memory CD4+ IL-21+ T cells in human PBMC%人外周血CD4+IL-21+记忆T细胞的特征

    Institute of Scientific and Technical Information of China (English)

    刘昀; 李丽; 黄凤玉; 吴长有

    2010-01-01

    目的:探讨人外周血中白细胞介索21(IL-21)的产生细胞及其特征.方法:分离人外周血单个核细胞(PBMC),分为不刺激或anti-CD3(OKT3)、OKT3+anti-CD28、PMA+ionomycin刺激四个组,流式细胞术(FCM)检测产生IL-21的细胞亚群.PMA+ionomycin刺激PBMC、纯化CD4+、CD4+CD45RA-、CD4+CD45RA+细胞、脐带血单个核细胞(CB-MC),FCM分析产生IL-21细胞的表型特征和IL-21与Th1、Th2、Th17和Th22细胞因子之间的关系.结果:与OKT3、OKT3+anti-CD28相比,PMA+ionomycin能诱导最高量的IL-21产生.产生IL-21的主要细胞为CD4+T细胞,少数CD8+T细胞.CD4+IL-21+T细胞表达CD45RO,不表达CD45RA,其中部分细胞表达CCR6、CCR7或CXCR5.CD4+CD45RA-细胞表达IL-21远高于CIM+CD45RA+细胞.进一步研究表明,PBMC产生IL-21,而CBMC不产生.此外,大约24%的CD4+IL-21+细胞表达IFN-γ,小于10%CD4+IL21+细胞表达IL-4、IL-17或IL-22.结论:人PBMC在多克隆刺激的条件下,可以诱导IL-21的产生.产生IL-21的主要细胞亚群具有记忆CD4+T细胞的表型.其中一部分CD4+IL-21+T细胞的表型独立于Th1、Th2、Th17和Th22细胞亚群.

  20. Regulatory activity of azabisphosphonate-capped dendrimers on human CD4+ T cell proliferation enhances ex-vivo expansion of NK cells from PBMCs for immunotherapy

    Directory of Open Access Journals (Sweden)

    Caminade Anne-Marie

    2009-09-01

    Full Text Available Abstract Background Adoptive cell therapy with allogenic NK cells constitutes a promising approach for the treatment of certain malignancies. Such strategies are currently limited by the requirement of an efficient protocol for NK cell expansion. We have developed a method using synthetic nanosized phosphonate-capped dendrimers allowing such expansion. We are showing here that this is due to a specific inhibitory activity towards CD4+ T cell which could lead to further medical applications of this dendrimer. Methods Mononuclear cells from human peripheral blood were used to investigate the immunomodulatory effects of nanosized phosphonate-capped dendrimers on interleukin-2 driven CD4+T cell expansion. Proliferation status was investigated using flow cytometry analysis of CFSE dilution and PI incorporation experiments. Magnetic bead cell sorting was used to address activity towards individual or mixed cell sub-populations. We performed equilibrium binding assay to assess the interaction of fluorescent dendrimers with pure CD4+ T cells. Results Phosphonate-capped dendrimers are inhibiting the activation, and therefore the proliferation; of CD4+ T cells in IL-2 stimulated PBMCs, without affecting their viability. This allows a rapid enrichment of NK cells and further expansion. We found that dendrimer acts directly on T cells, as their regulatory property is maintained when stimulating purified CD4+ T cells with anti-CD3/CD28 microbeads. Performing equilibrium binding assays using a fluorescent analogue, we show that the phosphonate capped-dendrimers are specifically interacting with purified CD4+ T cells. Ultimately, we found that our protocol prevents the IL-2 related expansion of regulatory T cells that would be deleterious for the activity of infused NK cells. Conclusion High yield expansion of NK cells from human PBMCs by phosphonate-capped dendrimers and IL-2 occurs through the specific inhibition of the CD4+ lymphocyte compartment. Given the

  1. Accelerated in vivo proliferation of memory phenotype CD4+ T-cells in human HIV-1 infection irrespective of viral chemokine co-receptor tropism.

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    Full Text Available CD4(+ T-cell loss is the hallmark of HIV-1 infection. CD4 counts fall more rapidly in advanced disease when CCR5-tropic viral strains tend to be replaced by X4-tropic viruses. We hypothesized: (i that the early dominance of CCR5-tropic viruses results from faster turnover rates of CCR5(+ cells, and (ii that X4-tropic strains exert greater pathogenicity by preferentially increasing turnover rates within the CXCR4(+ compartment. To test these hypotheses we measured in vivo turnover rates of CD4(+ T-cell subpopulations sorted by chemokine receptor expression, using in vivo deuterium-glucose labeling. Deuterium enrichment was modeled to derive in vivo proliferation (p and disappearance (d* rates which were related to viral tropism data. 13 healthy controls and 13 treatment-naive HIV-1-infected subjects (CD4 143-569 cells/ul participated. CCR5-expression defined a CD4(+ subpopulation of predominantly CD45R0(+ memory cells with accelerated in vivo proliferation (p = 2.50 vs 1.60%/d, CCR5(+ vs CCR5(-; healthy controls; P<0.01. Conversely, CXCR4 expression defined CD4(+ T-cells (predominantly CD45RA(+ naive cells with low turnover rates. The dominant effect of HIV infection was accelerated turnover of CCR5(+CD45R0(+CD4(+ memory T-cells (p = 5.16 vs 2.50%/d, HIV vs controls; P<0.05, naïve cells being relatively unaffected. Similar patterns were observed whether the dominant circulating HIV-1 strain was R5-tropic (n = 9 or X4-tropic (n = 4. Although numbers were small, X4-tropic viruses did not appear to specifically drive turnover of CXCR4-expressing cells (p = 0.54 vs 0.72 vs 0.44%/d in control, R5-tropic, and X4-tropic groups respectively. Our data are most consistent with models in which CD4(+ T-cell loss is primarily driven by non-specific immune activation.

  2. IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells

    DEFF Research Database (Denmark)

    Skov, S; Bonyhadi, M; Odum, Niels; Ledbetter, J A

    2000-01-01

    The cellular and humoral immune system is critically dependent upon CD40-CD154 (CD40 ligand) interactions between CD40 expressed on B cells, macrophages, and dendritic cells, and CD154 expressed primarily on CD4 T cells. Previous studies have shown that CD154 is transiently expressed on CD4 T cel...

  3. CD4 lymphocyte dynamics in Tanzanian pulmonary tuberculosis patients with and without HIV co-infection

    DEFF Research Database (Denmark)

    Andersen, Aase; Range, Nyagosya S; Changalucha, John;

    2012-01-01

    ABSTRACT: BACKGROUND: The interaction of HIV and tuberculosis (TB) on CD4 levels over time has previously been divergently reported and only in small study populations with short or no follow-up. METHODS: CD4 counts were assessed from time of diagnosis till the end of TB treatment in a cohort of ...

  4. HIV-specific CD4(+) T cells and viremia: who's in control?

    NARCIS (Netherlands)

    C.A. Jansen; D. van Baarle; F. Miedema

    2006-01-01

    It has been proposed that HIV-specific CD4(+) T cells with a central memory phenotype might be involved in controlling HIV replication. Based on recent data (lack of protective effects of HIV-specific CD4+ T-cell responses in acutely infected patients undergoing treatment interruptions; loss of init

  5. CD4 T cell activation and disease activity at onset of multiple sclerosis

    DEFF Research Database (Denmark)

    Jensen, J; Langkilde, Annika Reynberg; Fenst, C; Nicolaisen, M. S.; Roed, H. G.; Christensen, M; Sellebjerg, F

    We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease...

  6. Reactivity of naive CD4+CD25- T cells against gut microflora in healthy mice

    DEFF Research Database (Denmark)

    Gad, Monika; Lundsgaard, Dorthe; Kjellev, Stine;

    2006-01-01

    We have previously shown that conventional as well as germ-free CD4+ T cells depleted of CD25+ cells from the gut-associated lymphoid tissue and the periphery proliferate specifically in response to enterobacterial antigen exposure whereas unfractionated CD4+ T cells are not reactive under these ...

  7. STUDY ON CORRELATION OF CD4 COUNT WITH MALIGNANCY IN HIV

    Directory of Open Access Journals (Sweden)

    Kiran

    2015-08-01

    Full Text Available BACKGROUND: Malignancies are increasing in HIV patients and Opportunistic infections are decre asing with the use of ART (Anti - Retroviral Therapy. CD4 count is a simple immunological marker useful in HIV patients to assess the disease severity. The study was aimed to know whether CD4 count has any correlation with the incidence of malignancy in HIV patients . METHODOLOGY : Retrospective study was carried out; Using semi - structured proforma , data was collected from Medical Records Department. 40 HIV subjects diagnosed with malignancy was obtained. Fisher’s exact test was used to analyze the data stati st ically . RESULTS: In our study out of 40 subjects with malignancy 80% had CD4 count <200. Among the patients with AIDS defining malignancy 89% (16 patients had CD4 count<200. Among patients with Non A IDS defining malignancy , around 73% (16 patients had CD4 count<200. The association of type of malignancy with CD4 count is statistically not significant (p=0.358 but it has positive correlation. Out of 40 patients 21 were in HIV stage 4. Among the patie nts with stage 4 HIV , around 86% (18 had CD4 count<200. CONCLUSION : CD4 count has Positive correlation with the Incidence of Malignancy in HIV patients.

  8. Production of Primary Human CD4+ T Cell Lines and Clones

    OpenAIRE

    Matthis, Jessica; Reijonen, Helena

    2013-01-01

    Tetramer staining of CD4+ T cells is a valuable technique in immunology for detecting rare auto-reactive T cells. Generating clones or cell lines from auto-antigen tetramer positive CD4+ T cells allows further characterization and phenotyping of auto-reactive cells.

  9. CD4+CD25+Treg细胞与支气管哮喘%CD4+ CD25+ Treg cells and bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    鞠云飞; 孙立锋; 胡华

    2011-01-01

    The main function of CD4+ CD25+ Treg cells are immunological anergy and inhibition,which is essential to the maintenance of immunological tolerance in the host.CD4+ CD25+ Treg cells produce inhibitory cytokines (TGF-β and IL-10),express membrane molecules (CTLA-4,GITR,etc) and Foxp3.There are abnormal in function and quantity of CD4+ CD25+ Treg cells of peripheral blood from asthmatic patients,which maybe one of the pathogenesis of asthma.Glucocorticoids can inhibit the airway inflamation of asthma by impacting CD4+ CD25+ Treg cells.%CD4+ CD25+ Treg细胞的主要作用表现为免疫无能性和免疫抑制性,是外周免疫耐受形成机制的主要组成部分.其主要作用机制为分泌抑制性细胞因子(IL-10和TGF-β)、表达细胞表面分子(CTLA-4、GITR等)及Foxp3等.支气管哮喘患者外周血CD4+ CD25+ Treg功能及数量存在异常,这可能是支气管哮喘发病机制之一.糖皮质激素可以通过影响CD4+ CD25+ Treg的状态起到抑制支气管哮喘气道炎症的作用.

  10. AFM force measurements of the gp120-sCD4 and gp120 or CD4 antigen-antibody interactions

    International Nuclear Information System (INIS)

    Highlights: → The unbinding force of sCD4-gp120 interaction was 25.45 ± 20.46 pN. → The unbinding force of CD4 antigen-antibody interaction was 51.22 ± 34.64 pN. → The unbinding force of gp120 antigen-antibody interaction was 89.87 ± 44.63 pN. → The interaction forces between various HIV inhibitors and the target molecules are significantly different. → Functionalizing on AFM tip or substrate of an interaction pair caused different results. -- Abstract: Soluble CD4 (sCD4), anti-CD4 antibody, and anti-gp120 antibody have long been regarded as entry inhibitors in human immunodeficiency virus (HIV) therapy. However, the interactions between these HIV entry inhibitors and corresponding target molecules are still poorly understood. In this study, atomic force microscopy (AFM) was utilized to investigate the interaction forces among them. We found that the unbinding forces of sCD4-gp120 interaction, CD4 antigen-antibody interaction, and gp120 antigen-antibody interaction were 25.45 ± 20.46, 51.22 ± 34.64, and 89.87 ± 44.63 pN, respectively, which may provide important mechanical information for understanding the effects of viral entry inhibitors on HIV infection. Moreover, we found that the functionalization of an interaction pair on AFM tip or substrate significantly influenced the results, implying that we must perform AFM force measurement and analyze the data with more caution.

  11. Development and function of protective and pathologic memory CD4 T cells

    Directory of Open Access Journals (Sweden)

    Megan KL Macleod

    2015-09-01

    Full Text Available IImmunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naïve and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy.

  12. In situ depletion of CD4(+) T cells in human skin by Zanolimumab

    DEFF Research Database (Denmark)

    Villadsen, L.S.; Skov, L.; Dam, T.N.;

    2007-01-01

    -driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis......CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease...... xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4(+), but not...

  13. Label Free Detection of CD4+ and CD8+ T Cells Using the Optofluidic Ring Resonator

    Directory of Open Access Journals (Sweden)

    John T. Gohring

    2010-06-01

    Full Text Available We have demonstrated label free detection of CD4+ and CD8+ T-Lymphocyte whole cells and CD4+ T-Lymphocyte cell lysis using the optofluidic ring resonator (OFRR sensor. The OFRR sensing platform incorporates microfluidics and photonics in a setup that utilizes small sample volume and achieves a fast detection time. In this work, white blood cells were isolated from healthy blood and the concentrations were adjusted to match T-Lymphocyte levels of individuals infected with HIV. Detection was accomplished by immobilizing CD4 and CD8 antibodies on the inner surface of the OFRR. Sensing results show excellent detection of CD4+ and CD8+ T-Lymphocyte cells at medically significant concentrations with a detection time of approximately 30 minutes. This work will lead to a rapid and low-cost sensing device that can provide a CD4 and CD8 count as a measure of HIV progression.

  14. Correlation between Total Lymphocyte Count, Hemoglobin, Hematocrit and CD4 Count in HIV/AIDS Patients

    Directory of Open Access Journals (Sweden)

    Alavi S.M

    2009-04-01

    Full Text Available Lymphocyte CD4+count, a standard laboratory test for staging of HIV infection, is expensive and unavailable in resource-restricted countries. Total lymphocyte count (TLC and hemoglobin (Hb are recommended as simple & inexpensive surrogates. The aim of this study was to assess the correlation, sensitivity and predictive power of these parameters as substitutes for CD4 count. One hundred HIV patients enrolled in this analytic descriptive study in Ahvaz, a city in the South of Iran, from 2005 to 2006. They were tested for CD4 count, TLC, Hb, and hematocrit (Hct. The cutoffs were determined as: 200 cells/µL, 1200 cells/µL, 12 g/dl and 30%, respectively. We used Sys Max SE 9500 for CBC and Flow cytometry for CD4 count. The correlation coefficient established correlation between values. Sensitivity, specificity and positive predictive values were calculated. 2 females (%2 and 98 males (%98 of the mean age of 32±5 years were studied. 87 cases (%87 were IV drug users, the majority having a history of imprisonment. The mean CD4 count, TLC, Hb and Hct were 279±225, 2102±1250, 10.7±2.4 and 30.4±9.0, respectively. A strong correlation was observed between CD4 count and TLC (R = 0.645, P = 0.001, but no correlation was seen between CD4 count and Hb or Hct (R= 0.451, P=0.056 and R= 0.375, P=0.816 respectively. This study shows that TLC is a suitable surrogate marker for CD4 count. Hb and Hct are of limited value in predicting CD4 counts and should not be substituted for CD4counts.

  15. TRAIL对肿瘤侵润CD4+CD25+Treg的调节作用%Regulation of TRAIL on tumor infiltrating CD4+CD25+Treg

    Institute of Scientific and Technical Information of China (English)

    袁海芹; 刁智娟; 周剑锁; 刘彦信; 史娟; 郑德先

    2011-01-01

    0bjective:To investigate the regulation of TRAIL on tumor infiltrating CD 4+ CD25 +Treg cells.Methods:The inpact of TRAL on CCL22 secretion of tumor cells was detected by ELISA .Recam binant soluble TRAL was adminsttated into subcutaneous solid 4T1 tumor and tumor volum e was measured .Tumor infiltrating lym phocytes w ere isolated and assayed by flow cytam etry to evaluate the change of CD4+ CD25+ Treg cells in umor.Results:rsTRAIL increased CCL22 secretion into supematant of tumor cell 4Tl and B16 cells.TRAIL treat ment did notinhibit the s .C.4T1 tumor growth ,but turmor infiltrating CD 4+ CD25+ Treg increased obviously .Conclusion :Augmention in CCL22 secretion of 4T1 cancer cells might recruit Tregs,therefore, leading to turmor infiltrating CD 4+CD 25+Treg increase .This study provides novel data tor the physiological function research of TRAIL and cancer therapy application .%目的:探讨TRAIL对肿瘤侵润CD4+CD25+Treg细胞的调节作用.方法:ELISA检测TRAIL对肿瘤细胞分泌CCL22的影响;建立对TRAIL耐受的4T1肿瘤细胞皮下实体瘤模型,瘤内给予重组TRAIL蛋白,检测肿瘤体积的变化;分离肿瘤侵润的淋巴细胞,采用流式细胞术检测瘤内CD4+CD25+Treg细胞的变化.结果:TRAIL引起肿瘤细胞4T1和B16培养上清中CCL22水平增加;TRAIL治疗组与对照组相比,对TRAIL耐受的4T1移植瘤体积没有明显变化,但TRAIL治疗组的肿瘤侵润CD4+CD25+Treg细胞显著增加.结论:TRAIL引起肿瘤细胞分泌CCL22,可因此诱导CD4+CD25+Treg细胞趋化至肿瘤部位导致肿瘤侵润的CD4+CD25+Treg比例增加,为TRAIL的生理功能和在肿瘤治疗中的应用提供了新的资料.

  16. Immunity to experimental Salmonella typhimurium infections in rats. Transfer of immunity with primed CD4+CD25high and CD4+CD25low T lymphocytes

    DEFF Research Database (Denmark)

    Thygesen, P; Brandt, L; Jørgensen, T;

    1994-01-01

    The protective effect of primed CD4+ T lymphocytes against a lethal dose of 10(8) viable Salmonella typhimurium was studied in Lewis rats. Primed CD4+ T lymphocytes were obtained by inoculating Lewis rats with a non-lethal dose of 10(6) viable S. typhimurium. Four weeks after the infection, spleen...... fluorescence-activated cell sorter. Untreated Lewis rats were injected with 10(4) different primed CD4+ T-cell populations 24 h prior to the lethal dose of 10(8) viable S. typhimurium. Blood samples were drawn from the orbital plexus 1, 2, 3, and 4 weeks after the infection, and analysed for specific IgM and...... levels were not correlated with protection against S. typhimurium infections, although it showed that a higher and more persistent level of specific IgG antibodies was produced in animals receiving the CD4+CD25high fraction. It is concluded that 10(4) primed CD4+ T lymphocytes can induce immunity in...

  17. HIV-1 induces IL-10 production in human monocytes via a CD4-independent pathway.

    Science.gov (United States)

    Ji, Jiaxiang; Sahu, Gautam K; Braciale, Vivian L; Cloyd, Miles W

    2005-06-01

    In HIV-infected patients, increased levels of IL-10, mainly produced by virally infected monocytes, were reported to be associated with impaired cell-mediated immune responses. In this study, we investigated how HIV-1 induces IL-10 production in human monocytes. We found that CD14(+) monocytes infected by either HIV-1(213) (X4) or HIV-1(BaL) (R5) produced IL-10, IL-6, tumor necrosis factor-alpha (TNF-alpha), and to a lesser extent, IFN-gamma. However, the capacity of HIV-1 to induce these cytokines was not dependent on virus replication since UV-inactivated HIV-1 induced similar levels of these cytokines. In addition, soluble HIV-1 gp160 could induce CD14(+) monocytes to produce IL-10 but at lower levels. Cross-linking CD4 molecules (XLCD4) with anti-CD4 mAbs and goat anti-mouse IgG (GAM) resulted in high levels of IL-6, TNF-alpha and IFN-gamma but no IL-10 production by CD14(+) monocytes. Interestingly, neither anti-CD4 mAbs nor recombinant soluble CD4 (sCD4) receptor could block IL-10 secretion induced by HIV-1(213), HIV-1(BaL) or HIV-1 gp160 in CD14(+) monocytes, whereas anti-CD4 mAb or sCD4 almost completely blocked the secretion of the other cytokines. Furthermore, HIV-1(213) could induce IL-10 mRNA expression in CD14(+) monocytes while XLCD4 by anti-CD4 mAb and GAM failed to do so. As with IL-10 protein levels, HIV-1(213)-induced IL-10 mRNA expression in CD14(+) monocytes could not be inhibited by anti-CD4 mAb or sCD4. Taken together, HIV-1 binding to CD14(+) monocytes can induce CD4-independent IL-10 production at both mRNA and protein levels. This finding suggests that HIV induces the immunosuppressive IL-10 production in monocytes and is not dependent on CD4 molecules and that interference with HIV entry through CD4 molecules may have no impact on counteracting the effects of IL-10 during HIV infection. PMID:15937058

  18. Identification and Characterization of an Immunogenic Hybrid Epitope Formed by both HIV gp120 and Human CD4 Proteins ▿

    Science.gov (United States)

    Lewis, George K.; Fouts, Timothy R.; Ibrahim, Sani; Taylor, Brian M.; Salkar, Rachita; Guan, Yongjun; Kamin-Lewis, Roberta; DeVico, Anthony L.

    2011-01-01

    Certain antibodies from HIV-infected humans bind conserved transition state (CD4 induced [CD4i]) domains on the HIV envelope glycoprotein, gp120, and demonstrate extreme dependence on the formation of a gp120-human CD4 receptor complex. The epitopes recognized by these antibodies remain undefined although recent crystallographic studies of the anti-CD4i monoclonal antibody (MAb) 21c suggest that contacts with CD4 as well as gp120 might occur. Here, we explore the possibility of hybrid epitopes that demand the collaboration of both gp120 and CD4 residues to enable antibody reactivity. Analyses with a panel of human anti-CD4i MAbs and gp120-CD4 antigens with specific mutations in predicted binding domains revealed one putative hybrid epitope, defined by the human anti-CD4i MAb 19e. In virological and immunological tests, MAb 19e did not bind native or constrained gp120 except in the presence of CD4. This contrasted with other anti-CD4i MAbs, including MAb 21c, which bound unliganded, full-length gp120 held in a constrained conformation. Conversely, MAb 19e exhibited no specific reactivity with free human CD4. Computational modeling of MAb 19e interactions with gp120-CD4 complexes suggested a distinct binding profile involving antibody heavy chain interactions with CD4 and light chain interactions with gp120. In accordance, targeted mutations in CD4 based on this model specifically reduced MAb 19e interactions with stable gp120-CD4 complexes that retained reactivity with other anti-CD4i MAbs. These data represent a rare instance of an antibody response that is specific to a pathogen-host cell protein interaction and underscore the diversity of immunogenic CD4i epitope structures that exist during natural infection. PMID:21994452

  19. Blockade of Human Immunodeficiency Virus Type 1 Production in CD4^+ T Cells by an Intracellular CD4 Expressed Under Control of the Viral Long Terminal Repeat

    Science.gov (United States)

    Buonocore, Linda; Rose, John K.

    1993-04-01

    A retroviral vector was constructed in which a gene encoding a mutated soluble CD4 protein that is retained in the endoplasmic reticulum (sCD4-KDEL) is expressed under control of human immunodeficiency virus type 1 (HIV-1) regulatory elements. HIV-1 infection of a human T-cell line transduced with this vector led to induction of sCD4-KDEL synthesis and a block in transport of the HIV envelope protein to the cell surface. There was a complete block to maturation of infectious HIV-1 in the transduced cells, no viral spread, and little or no syncytium formation. Infected cells gradually disappeared from the culture over a period of 2 months. This intracellular trap for HIV has potential application in gene therapy for AIDS.

  20. CD4+CD25+Treg细胞与支气管哮喘%CD4+CD25+Treg cells and bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    鞠云飞; 孙立锋; 胡华

    2011-01-01

    CD4+CD25+Treg细胞的主要作用表现为免疫无能性和免疫抑制性,是外周免疫耐受形成机制的主要组成部分.其主要作用机制为分泌抑制性细胞因子(IL-10和TGF-β)、表达细胞表面分子(CTLA-4、GITR等)及Foxp3等.支气管哮喘患者外周血CD4+CD25+Treg功能及数量存在异常,这可能是支气管哮喘发病机制之一.糖皮质激素可以通过影响CD4+CD25+Treg的状态起到抑制支气管哮喘气道炎症的作用.

  1. Hierarchical Cd4SiS6/SiO2 Heterostructure Nanowire Arrays

    Directory of Open Access Journals (Sweden)

    Liu Jian

    2009-01-01

    Full Text Available Abstract Novel hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays were fabricated on silicon substrates by a one-step thermal evaporation of CdS powder. The as-grown products were characterized using scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. Studies reveal that a typical hierarchical Cd4SiS6/SiO2 heterostructure nanowire is composed of a single crystalline Cd4SiS6 nanowire core sheathed with amorphous SiO2 sheath. Furthermore, secondary nanostructures of SiO2 nanowires are highly dense grown on the primary Cd4SiS6 core-SiO2 sheath nanowires and formed hierarchical Cd4SiS6/SiO2 based heterostructure nanowire arrays which stand vertically on silicon substrates. The possible growth mechanism of hierarchical Cd4SiS6/SiO2 heterostructure nanowire arrays is proposed. The optical properties of hierarchical Cd4SiS6/SiO2 heterostructure nanowire arrays are investigated using Raman and Photoluminescence spectroscopy.

  2. Involvement of CD4+CD25+ regulatory T cells in the pathogenesis of polycythaemia vera

    Institute of Scientific and Technical Information of China (English)

    ZHAO Wen-bo; LI Ying; LIU Xin; ZHANG Ling-yan; WANG Xin

    2008-01-01

    Background Regulatory T cells (Treg) have been shown to play an important role in the regulation of hematopoietic activity. However, there is no information about the effect of Treg cells in the pathogenesis of polycythaemia vera (PV).Methods In this study, we investigated the percentage and function of Treg cells in the peripheral blood of 21 PV patients and 25 healthy donors. Treg cells were identified and characterized as CD4+CD25+FOXP3+ by flow cytometry.The suppressive activity of CD4+CD25+ Treg cells was assessed by the proliferation and cytokine secretion of the co-cultured CD4+CD25- fractions.Results The results showed that the percentage of Treg cells in the peripheral blood of PV patients significantly increased compared to healthy controls ((10.93±4.02)% vs (5.86±1.99)%, P <0.05). Moreover, the mRNA and protein expression of FOXP3 was higher in CD4+CD25+ Treg cells. Coordinately, when co-cultured with the activated CD4+CD25-cells, the CD4+CD25+ Treg cells showed enhanced suppressive function in PV. Yet, the underlying mechanism for the increased frequency and function of CD4+CD25+ Treg cells is still to be clarified.Conclusion Treg cells expansion might account for the abnormal T cell immunity in PV patients and thus contribute to the pathogenesis of PV.

  3. Distribution of CD4 lymphocyte cells among apparently healthy HIV seropositive and seronegative populations

    Directory of Open Access Journals (Sweden)

    Abdulazeez A Abubakar

    2012-01-01

    Full Text Available Background: CD4 lymphocyte cells are often used as prognostic markers for monitoring the progression of immunosupression such as HIV infection. Aim: This study was conducted to assess the distribution of CD4 lymphocytes among apparently healthy human immunodeficiency virus (HIV seronegative and seropositive populations in a Nigerian state. Materials and Methods: A total of 1520 apparently healthy subjects aged 18-64 years, composed of 800 males and 720 females attending some selected health institutions in the state, participated in the study. Ten milliliters of blood was collected from each subject; 5 ml of this was used for HIV antibodies sero-typing while the remaining 5 ml was anticoagulated and used for CD4 lymphocytes level determination. Only samples tested positive both with Capillus and Determine HIV test kits were further differentiated into sero-types with a standard diagnostic HIV test kit. The CD4 lymphocyte levels of all the sample were determined; mean CD4 levels of 205.1±0.09 and 287.4±0.3 cells/μl were recorded among females seropositives and seronagatives respectively. Statistical analysis by the Student t-test showed a significant difference in the mean CD4 lymphocyte count by gender. Results: Findings showed a mean CD4 level of 311.7±1.2 cells/μl among seropositive males while 399.3±0.6 cells/μl was recorded among seronegatives (t=5.86. The study also recorded a CD4 lymphocyte range of 232-464 cells/μl among apparently healthy seronegative population in this locality. Conclusion: The findings showed a significantly higher mean CD4 lymphocyte count among adult male HIV seronegatives (χ2= 9.22 and seropositives (χ2=15.07 than their female counterparts. Further research work using the automation technique is suggested to confirm this new range for monitoring HIV subjects on antiretroviral therapy.

  4. Modeling the Slow CD4+ T Cell Decline in HIV-Infected Individuals.

    Science.gov (United States)

    Wang, Sunpeng; Hottz, Patricia; Schechter, Mauro; Rong, Libin

    2015-12-01

    The progressive loss of CD4+ T cell population is the hallmark of HIV-1 infection but the mechanism underlying the slow T cell decline remains unclear. Some recent studies suggested that pyroptosis, a form of programmed cell death triggered during abortive HIV infection, is associated with the release of inflammatory cytokines, which can attract more CD4+ T cells to be infected. In this paper, we developed mathematical models to study whether this mechanism can explain the time scale of CD4+ T cell decline during HIV infection. Simulations of the models showed that cytokine induced T cell movement can explain the very slow decline of CD4+ T cells within untreated patients. The long-term CD4+ T cell dynamics predicted by the models were shown to be consistent with available data from patients in Rio de Janeiro, Brazil. Highly active antiretroviral therapy has the potential to restore the CD4+ T cell population but CD4+ response depends on the effectiveness of the therapy, when the therapy is initiated, and whether there are drug sanctuary sites. The model also showed that chronic inflammation induced by pyroptosis may facilitate persistence of the HIV latent reservoir by promoting homeostatic proliferation of memory CD4+ cells. These results improve our understanding of the long-term T cell dynamics in HIV-1 infection, and support that new treatment strategies, such as the use of caspase-1 inhibitors that inhibit pyroptosis, may maintain the CD4+ T cell population and reduce the latent reservoir size. PMID:26709961

  5. Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL.

    Science.gov (United States)

    Sande, Obondo J; Karim, Ahmad F; Li, Qing; Ding, Xuedong; Harding, Clifford V; Rojas, Roxana E; Boom, W Henry

    2016-01-15

    Mycobacterium tuberculosis cell wall glycolipid, lipoarabinomannan, can inhibit CD4(+) T cell activation by downregulating the phosphorylation of key proximal TCR signaling molecules: Lck, CD3ζ, ZAP70, and LAT. Inhibition of proximal TCR signaling can result in T cell anergy, in which T cells are inactivated following an Ag encounter, yet remain viable and hyporesponsive. We tested whether mannose-capped lipoarabinomannan (LAM)-induced inhibition of CD4(+) T cell activation resulted in CD4(+) T cell anergy. The presence of LAM during primary stimulation of P25 TCR-transgenic murine CD4(+) T cells with M. tuberculosis Ag85B peptide resulted in decreased proliferation and IL-2 production. P25 TCR-transgenic CD4(+) T cells primed in the presence of LAM also exhibited decreased response upon restimulation with Ag85B. The T cell anergic state persisted after the removal of LAM. Hyporesponsiveness to restimulation was not due to apoptosis, generation of Foxp3-positive regulatory T cells, or inhibitory cytokines. Acquisition of the anergic phenotype correlated with upregulation of gene related to anergy in lymphocytes (GRAIL) protein in CD4(+) T cells. Inhibition of human CD4(+) T cell activation by LAM also was associated with increased GRAIL expression. Small interfering RNA-mediated knockdown of GRAIL before LAM treatment abrogated LAM-induced hyporesponsiveness. In addition, exogenous IL-2 reversed defective proliferation by downregulating GRAIL expression. These results demonstrate that LAM upregulates GRAIL to induce anergy in Ag-reactive CD4(+) T cells. Induction of CD4(+) T cell anergy by LAM may represent one mechanism by which M. tuberculosis evades T cell recognition. PMID:26667170

  6. Cervical radiculopathy.

    Science.gov (United States)

    Iyer, Sravisht; Kim, Han Jo

    2016-09-01

    Cervical radiculopathy is a common clinical scenario. Patients with radiculopathy typically present with neck pain, arm pain, or both. We review the epidemiology of cervical radiculopathy and discuss the diagnosis of this condition. This includes an overview of the pertinent findings on the patient history and physical examination. We also discuss relevant clinical syndromes that must be considered in the differential diagnosis including peripheral nerve entrapment syndromes and shoulder pathology. The natural history of cervical radiculopathy is reviewed and options for management are discussed. These options include conservative management, non-operative modalities such as physical therapy, steroid injections, and operative intervention. While the exact indications for surgical intervention have not yet been elucidated, we provide an overview of the available literature regarding indications and discuss the timing of intervention. The surgical outcomes of anterior cervical decompression and fusion (ACDF), cervical disc arthroplasty (CDA), and posterior cervical foraminotomy (PCF) are discussed. PMID:27250042

  7. Detection of resistance mutations and CD4 slopes in individuals experiencing sustained virological failure

    Directory of Open Access Journals (Sweden)

    Anna Schultze

    2014-11-01

    Full Text Available Introduction: Several resistance mutations have been shown to affect viral fitness, and the presence of certain mutations might result in clinical benefit for patients kept on a virologically failing regimen due to an exhaustion of drug options. We sought to quantify the effect of resistance mutations on CD4 slopes in patients undergoing episodes of viral failure. Materials and Methods: Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART with at least three CD4 measurements and a resistance test during the episode were included. Mutations were identified using the IAS-US (2013 list, and were presumed to be present from detection until the end of an episode. Multivariable linear mixed models with a random intercept and slope adjusted for age, baseline CD4 count, hepatitis C, drug type, RNA (log-scale, risk group and subtype were used to estimate CD4 slopes. Individual mutations with a population prevalence of >10% were tested for their effect on the CD4 slope. Results: A total of 2731 patients experiencing a median of 1 (range 1–4 episodes were included in this analysis. The prevalence of any resistance per episode was 88.4%; NNRTI resistance was most common (78.5%. Overall, CD4 counts declined by 17.1 (−19.7; −14.5 cells per year; this decline was less marked with partial viral suppression (current HIV RNA more than 1.5 log below the setpoint; p=0.01. In multivariable models adjusting for viral load, CD4 decline was slower during episodes with detected resistance compared to episodes without detected resistance (21.0 cells/year less, 95% CI 11.75–30.31, p<0.001. Among those with more than one resistance mutation, there was only weak evidence that class-specific mutations had any effect on the CD4 slope (Table 1. The effects of individual mutations (incl. M184V were explored, but none were significantly associated with the CD4 slope; for these

  8. Progressive multifocal leucoencephalopathy in a patient with idiopathic CD4+ lymphocytopenia.

    LENUS (Irish Health Repository)

    Moloney, F

    2012-03-01

    Progressive multifocal leucoencephalopathy (PML) is an opportunistic, demyelinating neurological disease caused by reactivation of the JC polyomavirus. PML occurs almost exclusively in immunosuppressed individuals, with only isolated case reports of PML occurring in patients without apparent immunosuppression. Idiopathic CD4+ lymohocytopenia (ICL) is a syndrome defined by the Centre for Disease Control and Prevention as a CD4+ count <300 cells\\/uL or <20% of total T cell count on >1 occasion, with no evidence of human immunodeficiency virus (HIV) infection, and the absence of other known immunodeficiency or therapy associated with lymphocytopenia. We describe a case of PML occurring in a patient with idiopathic CD4+ lymphocytopenia.

  9. Idiopathic CD4 lymphocytopenia with giant cell arteritis and pulmonary mucormycosis

    Directory of Open Access Journals (Sweden)

    Ryan A. Denu

    2014-10-01

    Full Text Available Idiopathic CD4 lymphocytopenia (ICL is characterized by a low CD4+ lymphocyte count in the absence of HIV or other underlying etiologies. We report a case of a 57-year old man with ICL and giant cell arteritis (GCA who developed pulmonary mucormycosis, which, to our knowledge, is the first report of these occurring in a patient with ICL. Abnormally low total lymphocyte or CD4+ cell counts occurring in patients with autoimmune disorders should alert clinicians to the possibility of ICL. Immunosuppressive treatment should be used with caution in this context.

  10. Interleukin 1-induced down-regulation of antibody binding to CD4 molecules on human lymphocytes

    DEFF Research Database (Denmark)

    Tvede, N; Christensen, L D; Ødum, Niels;

    1988-01-01

    Interleukin 1 (IL-1) is involved in the early activation of T lymphocytes. The CD4 antigen, described as a phenotypic marker of helper T cells, is also important in early T-cell activation by its ability to bind to MHC class II molecules on antigen-presenting cells, and to transmit positive (and ...... actinomycin D or cytochalasin B, indicating that protein synthesis and intact microfilament function were essential for re-expression of CD4 binding. The mechanism by which CD4 molecules are physically and/or functionally modulated by IL-1 is unclear....

  11. CCL2 Increases X4-tropic HIV-1 Entry into Resting CD4+ T Cells*

    OpenAIRE

    Campbell, Grant R.; Spector, Stephen A.

    2008-01-01

    During human immunodeficiency virus type 1 (HIV-1) infection, there is a strong positive correlation between CCL2 levels and HIV viral load. To determine whether CCL2 alters HIV-1 infection of resting CD4+ T cells, we infected purified resting CD4+ T cells after incubation with CCL2. We show that CCL2 up-regulates CXCR4 on resting CD4+ T cells in a CCR2-dependent mechanism, and that this augmentation of CXCR4 expression by CCL2 increases the ability of these cells to b...

  12. Genetic subspecies diversity of the chimpanzee CD4 virus-receptor gene

    DEFF Research Database (Denmark)

    Hvilsom, Christina; Carlsen, Frands; Siegismund, Hans R;

    2008-01-01

    Chimpanzees are naturally and asymptomatically infected by simian immunodeficiency virus (SIV). Pathogenic properties of SIV/HIV vary and differences in susceptibility and pathogenicity of SIV/HIV depend in part on host-specific factors such as virus-receptor/co-receptor interactions. Since CD4...... plays a primary role in virus binding and since SIVcpz have been found only in two African chimpanzee subspecies, we characterized the genetic diversity of CD4 receptors in all four recognized subspecies of chimpanzees. We found noticeable variation in the first variable region V1 of CD4 and in intron...

  13. Gads-deficient thymocytes are blocked at the transitional single positive CD4+ stage

    OpenAIRE

    Dalheimer, Stacy L.; Zeng, Ling; Draves, Kevin E.; Hassaballa, Ashraf; Jiwa, Nasheena N.; Parrish, Torrey D.; Edward A Clark; Yankee, Thomas M.

    2009-01-01

    Positive selection of T cell precursors is the process by which a diverse T cell repertoire is established. Positive selection begins at the CD4+CD8+ double positive (DP) stage of development and involves at least two steps. First, DP thymocytes downregulate CD8 to become transitional single positive (TSP) CD4+ thymocytes. Then, cells are selected to become either mature SP CD4+ or mature SP CD8+ thymocytes. We sought to define the function of Gads during the two steps of positive selection b...

  14. Viral load profiles in drug users with asymptomatic HIV infection and normal CD4 cell counts

    OpenAIRE

    Zubairi Djoerban

    2002-01-01

    Since the year 2000 there has been a steep increased in the number of HIV/AIDS patients in Indonesia, coming mostly from intravenous drug users. Antiretroviral treatment has been proved to decrease mortality and increase quality of life of HIV/AIDS patients. The treatment is given according to clinical condition of the patients, number of CD4 and viral load. In this study, CD4 and viral load were examined in 71 asymptomatic HIV patients originated from injecting-drug users. CD4 counting was p...

  15. Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation.

    Directory of Open Access Journals (Sweden)

    Emma M Quinn

    Full Text Available Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; P(adjusted = 2.40x10(-11 in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (P(adjusted = 0.002, and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P<2.2x10(-16 and highlighted IFNy and the genetically associated transcription factor BACH2 which showed significantly reduced expression in coeliac samples (log2FC -1.75; P(adjusted = 3.6x10(-3 as key regulatory genes in CD. Genes regulated by BACH2 were very significantly over-represented among our differentially expressed genes (P<2.2x10(-16 indicating that reduced expression of this master regulator of T cell differentiation promotes a pro-inflammatory response and strongly corroborates genetic evidence that BACH2 plays an important role in CD pathogenesis.

  16. Interleukin-2 Enhances the Regulatory Functions of CD4(+)T Cell-Derived CD4(-)CD8(-) Double Negative T Cells.

    Science.gov (United States)

    Cong, Min; Liu, Tianhui; Tian, Dan; Guo, Hongbo; Wang, Ping; Liu, Kai; Lin, Jun; Tian, Yue; Shi, Wen; You, Hong; Jia, Jidong; Zhang, Dong

    2016-08-01

    CD4(+) T cells can be converted to CD4(-)CD8(-) double negative T cells (DN T cells) under appropriate conditions, and IL-2 enhanced the conversion. Here, we investigated the effect of IL-2 on the proliferation and function of converted DN T cells in vitro and in vivo. DN T cells were hyporesponsive when restimulated by mature dendritic cells (mDCs), IL-2 completely restored their responsiveness in vitro. In addition, IL-2 increased the resistance of DN T cells to apoptosis in vivo. DN T cells profoundly inhibited the proliferation of CD4(+)CD25(-) T effector cells triggered by mDCs in vitro, and this suppression was further enhanced by IL-2. Adoptively transferring of DN T cells, in combination with IL-2, inhibited the proliferation and enhanced apoptosis of alloreactive CD4(+) T cells, which resulted in significant prolongation of skin allograft survival time. Perforin plays a key role in the enhancement of DN T cells immune regulation by IL-2. In conclusion, we elucidated that IL-2 promoted DN T cell proliferation and suppressive function. The combination of DN T cells and exogenous IL-2 may represent a novel therapy in the clinical setting to prevent allograft rejection and induce immune tolerance. PMID:27135902

  17. Fine needle aspiration cytology study of HIV lymphadenopathy and its correlation with CD4 count

    Directory of Open Access Journals (Sweden)

    Jayshree Khiste

    2015-10-01

    Results: Out of 64 cases, Tuberculosis (TB lymphadenitis was the most common lesion with 47.05% cases and its mean CD4 count was 329/ul. There were 4 cases of malignancy; two were that of primary malignancy - lymphoma and other two were metastasis from epithelial malignancies. Conclusions: FNAC is a simple and rapid investigative technique to differentiate and diagnose various causes of lymphadenopathy. TB lymphadenitis is the most common lesion associated with HIV positive patients. CD4 counts correlate well with underlying lymph node pathology, TB lymphadenitis being common in CD4 range of 200-500/ul and HIV associated malignancies seen in CD4 count less than 100/ul. [Int J Res Med Sci 2015; 3(10.000: 2635-2638

  18. Human CD141+ DCs induce CD4+ T cells to produce type 2 cytokines1

    Science.gov (United States)

    Yu, Chun I; Becker, Christian; Metang, Patrick; Marches, Florentina; Wang, Yuanyuan; Toshiyuki, Hori; Banchereau, Jacques; Merad, Miriam; Palucka, Karolina

    2014-01-01

    Dendritic cells (DCs) play the central role in the priming of naïve T cells and the differentiation of unique effector T cells. Here, using lung tissues and blood from both humans and humanized mice, we analyzed the response of human CD1c+ and CD141+ DC subsets to live-attenuated influenza virus (LAIV). Specifically, we analyzed the type of CD4+ T cell immunity elicited by LAIV-exposed DCs. Both DC subsets induce proliferation of allogeneic naïve CD4+ T cells with capacity to secrete IFN-γ. However, CD141+ DCs are uniquely able to induce the differentiation of IL-4 and IL-13 producing CD4+ T cells. CD141+ DCs induce IL-4 and IL-13 secreting CD4+ T cells through OX40L. Thus, CD141+ DCs demonstrate remarkable plasticity in guiding adaptive immune responses. PMID:25246496

  19. The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex

    Science.gov (United States)

    Nandy, Bidisha; Saurabh, Suman; Sahoo, Anil Kumar; Dixit, Narendra M.; Maiti, Prabal K.

    2015-11-01

    The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry.The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude

  20. Natural CD4+ T-cell responses against indoleamine 2,3-dioxygenase.

    Directory of Open Access Journals (Sweden)

    Shamaila Munir

    Full Text Available BACKGROUND: The enzyme indoleamine 2,3-dioxygenase (IDO contributes to immune tolerance in a variety of settings. In cancer IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it endorses the establishment of peripheral immune tolerance to tumor antigens. Recently, we described cytotoxic CD8(+ T-cell reactivity towards IDO-derived peptides. METHODS AND FINDINGS: In the present study, we show that CD4(+ helper T cells additionally spontaneously recognize IDO. Hence, we scrutinized the vicinity of the previously described HLA-A*0201-restricted IDO-epitope for CD4(+ T-cell epitopes. We demonstrated the presence of naturally occurring IDO-specific CD4(+ T cells in cancer patients and to a lesser extent in healthy donors by cytokine release ELISPOT. IDO-reactive CD4(+ T cells released IFN-γ, TNF-α, as well as IL-17. We confirm HLA class II-restriction by the addition of HLA class II specific blocking antibodies. In addition, we detected a trend between class I- and class II-restricted IDO responses and detected an association between IDO-specific CD4(+ T cells and CD8(+ CMV-responses. Finally, we could detect IL-10 releasing IDO-reactive CD4(+ T cells. CONCLUSION: IDO is spontaneously recognized by HLA class II-restricted, CD4(+ T cells in cancer patients and in healthy individuals. IDO-specific T cells may participate in immune-regulatory networks where the activation of pro-inflammatory IDO-specific CD4(+ responses may well overcome or delay the immune suppressive actions of the IDO-protein, which are otherwise a consequence of the early expression of IDO in maturing antigen presenting cells. In contrast, IDO-specific regulatory T cells may enhance IDO-mediated immune suppression.

  1. CD4+ lymphoid tissue inducer cells promote innate immunity in the gut

    OpenAIRE

    Sonnenberg, Gregory F.; Monticelli, Laurel A.; Elloso, M. Merle; Fouser, Lynette A.; Artis, David

    2010-01-01

    Fetal CD4+ lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid-tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that following infection with Citrobacter rodentium, CD4+ LTi cells were a dominant source of interleukin-...

  2. CORRELATION BETWEEN CLINICAL PROFILE, CD 4 COUNT AND TOTAL LYMPHOCYTE COUNT IN HIV INFECTED PERSONS

    Directory of Open Access Journals (Sweden)

    Keshava

    2014-01-01

    Full Text Available BACKGROUND & OBJECTIVES: HIV infection can be monitored by laboratory and clinical markers of disease progression. In the absence of CD 4 count , the use of Total Lymphocyte Count has been advocated to predict CD 4 count and to stage HIV disease. This study was undertaken to show whether the TLC accurately predicts a low CD 4 count in HIV infected persons and its clinical correlation. METHODOLOGY: The data for the study was collected from HIV positive inpatients and outpatients of KIMS Hospital , Bangalore fr om March 2004 to March 2006. A total 50 patients were subjected to clinical examination and relevant investigations including CD 4 Count and TLC. RESULTS: In our study , males (39 , outnumbered females (11. The major risk factor for HIV infection in these patients was unprotected , multiple sexual contacts. Fever , Anorexia , Weight loss , Lethargy , Cough , Diarrhea and Mouth ulcers were the common presenting symptoms. Tuberculosis , Chronic diarrhea , Oropharyngeal candidiasis were the most common opportunistic i nfections. Majority of the patients had CD 4 Count less than 350 cells/μl and were symptomatic. The Total Lymphocyte Counts of 1750 cells/μl and 2450 cells/μl correlated to CD 4 counts of 200 cells/μl and 350 cells/μl respectively. INTERPRETATION & CONCLUS ION: There was a highly significant correlation between CD 4 Count and Total Lymphocyte Count. TLC can be used as an effective laboratory tool to monitor disease progression in HIV infected persons where CD 4 is not available and in resource poor countries .

  3. Effects of estrogen on CD4+CD25+ regulatory T cell in peripheral blood during pregnancy

    Institute of Scientific and Technical Information of China (English)

    Yuan-Huan Xiong; Zhen Yuan; Li He

    2013-01-01

    Objective:To investigate the effects of estrogen (E2) level on regulatory T cells (Treg) in peripheral blood during pregnancy. Methods:A total of 30 healthy non-pregnant women were selected as control group, 90 pregnant women of early, middle and late pregnancy and 30 postpartum women at 1 month after parturition were selected as experimental groups including early pregnancy group, middle pregnancy group and late pregnancy group;the proportions of CD4+CD25+Treg and CD4+CD25+CD127-Treg among CD4+T cells were detected by flow cytometry;the serum estrogen content in peripheral blood was detected by electrochemical immune luminescence method. Results: E2 level was coincident with the change of Tregs number during pregnancy. The estrogen content in peripheral blood increased gradually from early pregnancy to late pregnancy, then decreased significantly after parturition, and the level at 1 month after parturition down to the level in non-pregnancy group (P>0.05);the level of E2 in pregnancy groups were significantly higher than those in non-pregnancy group (P0.05);the proportions in middle and late pregnancy groups were significantly higher than those in early pregnancy group (P0.05). There was correlation between Tregs number with estrogen level during pregnancy. The proportion of CD4+CD25+ Treg and CD4+CD25+CD127- Treg were positively correlated with estrogen level. Conclusions:High proportion of CD4+CD25+Treg and CD4+CD25+CD127-Treg is closely related to the high level of E2 during pregnancy. It suggested that high level of estrogen may induce an increase of CD4+CD25+Treg in peripheral blood, and then influence the immune function of pregnant women. The results of this experiment might play an important role of estrogen in immune-modulation during pregnancy.

  4. A subset of memory CD4+ helper T lymphocytes identified by expression of Pgp-1

    OpenAIRE

    1989-01-01

    The Pgp-1 glycoprotein (Ly-24 antigen) is acquired by mature murine T lymphocytes at the time of primary antigen stimulation Pgp-1 was previously shown to be a useful cell surface marker for distinguishing antigen-specific memory CD8+ T lymphocytes after immunization. Here we demonstrate that this observation extends to CD4+ T lymphocytes. Antigen-specific CD4+ T cells in mice immunized with sperm whale myoglobin or keyhole limpet hemocyanin were contained nearly exclusively in the minor Pgp-...

  5. The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

    OpenAIRE

    Haxhinasto, Sokol; Mathis, Diane; Benoist, Christophe

    2008-01-01

    CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially dimi...

  6. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Kara G Lassen

    2006-07-01

    Full Text Available HIV-1 latency in resting CD4+ T cells represents a major barrier to virus eradication in patients on highly active antiretroviral therapy (HAART. We describe here a novel post-transcriptional block in HIV-1 gene expression in resting CD4+ T cells from patients on HAART. This block involves the aberrant localization of multiply spliced (MS HIV-1 RNAs encoding the critical positive regulators Tat and Rev. Although these RNAs had no previously described export defect, we show that they exhibit strict nuclear localization in resting CD4+ T cells from patients on HAART. Overexpression of the transcriptional activator Tat from non-HIV vectors allowed virus production in these cells. Thus, the nuclear retention of MS HIV-1 RNA interrupts a positive feedback loop and contributes to the non-productive nature of infection of resting CD4+ T cells. To define the mechanism of nuclear retention, proteomic analysis was used to identify proteins that bind MS HIV-1 RNA. Polypyrimidine tract binding protein (PTB was identified as an HIV-1 RNA-binding protein differentially expressed in resting and activated CD4+ T cells. Overexpression of PTB in resting CD4+ T cells from patients on HAART allowed cytoplasmic accumulation of HIV-1 RNAs. PTB overexpression also induced virus production by resting CD4+ T cells. Virus culture experiments showed that overexpression of PTB in resting CD4+ T cells from patients on HAART allowed release of replication-competent virus, while preserving a resting cellular phenotype. Whether through effects on RNA export or another mechanism, the ability of PTB to reverse latency without inducing cellular activation is a result with therapeutic implications.

  7. CD4+ T cells mediate mucosal and systemic immune responses to experimental hookworm infection

    OpenAIRE

    DONDJI, B.; Sun, T.; BUNGIRO, R. D.; VERMEIRE, J. J.; HARRISON, L. M.; BIFULCO, C.; Cappello, M

    2010-01-01

    Hookworm infection is associated with anaemia and malnutrition in many resource-limited countries. Ancylostoma hookworms have previously been shown to modulate host cellular immune responses through multiple mechanisms, including reduced mitogen-mediated lymphocyte proliferation, impaired antigen presentation/processing, and relative reductions in CD4+ T cells in the spleen and mesenteric lymph nodes. Syrian hamsters were depleted of CD4+ for up to 9 days following intraperitoneal injection (...

  8. Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.

    Directory of Open Access Journals (Sweden)

    Michaela Lucas

    Full Text Available BACKGROUND: CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. METHODOLOGY/PRINCIPAL FINDINGS: Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. CONCLUSIONS/SIGNIFICANCE: During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.

  9. In Vivo Identification and Characterization of CD4+ Cytotoxic T Cells Induced by Virulent Brucella abortus Infection

    OpenAIRE

    Martirosyan, Anna; von Bargen, Kristine; Arce Gorvel, Vilma; Zhao, Weidong; Hanniffy, Sean; Bonnardel, Johnny; Méresse, Stéphane; Gorvel, Jean-Pierre

    2013-01-01

    CD4+ T cells display a variety of helper functions necessary for an efficient adaptive immune response against bacterial invaders. This work reports the in vivo identification and characterization of murine cytotoxic CD4+ T cells (CD4+ CTL) during Brucella abortus infection. These CD4+ CTLs express granzyme B and exhibit immunophenotypic features consistent with fully differentiated T cells. They express CD25, CD44, CD62L ,CD43 molecules at their surface and produce IFN-γ. Moreover, these cel...

  10. Effect of melatonin on CD4+ T cell proliferation and the activity of Foxp3 promoter in mice%褪黑素对小鼠CD4+T细胞增殖及Foxp3启动子活性的影响

    Institute of Scientific and Technical Information of China (English)

    刘卉; 徐丽; 王日雄; 张慧; 周瑞祥

    2012-01-01

    目的 探讨褪黑素(melatonin,MLT)对小鼠CD4+T细胞增殖及Foxp3 (Forkhead box P3)启动子活性的影响,进一步丰富神经内分泌免疫网络学说.方法 免疫磁珠分选小鼠脾CD4+T细胞,CCK-8法检测褪黑素对其增殖活性的影响;构建、筛选及鉴定Foxp3核心和全长启动子重组载体,并且电转染入小鼠CD4+T细胞,加以不同淋巴细胞刺激因子和褪黑素干预,用双荧光素酶报告基因法检测Foxp3启动子的活性变化.结果 与空白对照组相比,从10-5 mol浓度的MLT开始对CD4+T细胞有毒性作用,并呈剂量依赖性.10-6 mol MLT对CD4+T细胞的增殖活性无影响.3种淋巴细胞刺激因子(佛波酯PMA+离子霉素ionomycin;植物血凝素PHA;T细胞抗原受体TCR)刺激和(或)褪黑素干预虽然使小鼠Foxp3核心或全长启动子活性有所上调,但与空白对照差异无统计学意义(P>0.05).结论 不同浓度褪黑素对小鼠CD4+T细胞增殖活性产生不同影响;褪黑素未显著增强小鼠Foxp3启动子活性.%Objective To investigate the effect of melatonin on CD4+T cell proliferation and promoter activity of Foxp3 in mice, which further enrich the theory of neuroendocrine-immune network. Methods Purified CD4+T cells were isolated from spleen using magnetic beads for the negative selection process. The effect of melatonin on CD4+ T cell proliferation by using CCK-8 method. Construction and identification of reeombinant plasmids of the core and full length for Foxp3 promoter, which electroporated into CD4+T cells using the Nucleofector. Then the cells stimulated with different kinds of lymphatic stimulatory substances and intervented by melatonin. Finally, luciferase activity was measured by the dual luciferase assay system. Results Compared with the blank control, from 10-5 mol concentration of MLT begin to be poisonous for CD4+ T cell, which exhibited a dose dependent. And 10-6 mol concentration of MLT has no effect on cell proliferation. Three kinds

  11. Aire-Overexpressing Dendritic Cells Induce Peripheral CD4+ T Cell Tolerance

    Science.gov (United States)

    Li, Dongbei; Li, Haijun; Fu, Haiying; Niu, Kunwei; Guo, Yantong; Guo, Chuan; Sun, Jitong; Li, Yi; Yang, Wei

    2015-01-01

    Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study’s aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4+ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4+ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4+ IFN-γ+ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca2+ and p-ERK) in CD4+ T cells. We observed that Aire cells-induced CD4+ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4+IFN-γ+ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire. PMID:26729097

  12. Operational challenges in delivering CD4 diagnostics in sub-Saharan Africa.

    Science.gov (United States)

    Thairu, L; Katzenstein, D; Israelski, D

    2011-07-01

    Access to reliable and low cost CD4 T-cell enumeration to stage illness and monitor anti-retroviral therapy remains elusive in resource-limited settings. We report challenges in delivering CD4 testing using the microcapillary Fluorescence-Activated Cell Sorter (FACS) methodology (Guava EasyCD4 instrument Guava Technologies, Hayward) in Burkina Faso and Zimbabwe. Resources, instruments, reagents, and training were provided to local laboratories within the existing infrastructure and data on CD4 were collected from routine laboratory testing. Challenges encountered included frequent instrument breakdown; poor manufacturer maintenance; difficulties in managing reagent stocks; high technician turnover; reliance on antiquated data management systems; redundant service provision; and lack of repeat testing in male HIV+ patients and in patients with higher CD4 counts after initial staging. While adopting newer, less expensive technologies such as fluorescent platforms and point of care tests can facilitate access to lower cost CD4 testing, our experience suggests that supply chain, corporate commitment to implementation, and community factors also require consideration. PMID:21400312

  13. Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors.

    Science.gov (United States)

    Zhou, Tongqing; Lynch, Rebecca M; Chen, Lei; Acharya, Priyamvada; Wu, Xueling; Doria-Rose, Nicole A; Joyce, M Gordon; Lingwood, Daniel; Soto, Cinque; Bailer, Robert T; Ernandes, Michael J; Kong, Rui; Longo, Nancy S; Louder, Mark K; McKee, Krisha; O'Dell, Sijy; Schmidt, Stephen D; Tran, Lillian; Yang, Zhongjia; Druz, Aliaksandr; Luongo, Timothy S; Moquin, Stephanie; Srivatsan, Sanjay; Yang, Yongping; Zhang, Baoshan; Zheng, Anqi; Pancera, Marie; Kirys, Tatsiana; Georgiev, Ivelin S; Gindin, Tatyana; Peng, Hung-Pin; Yang, An-Suei; Mullikin, James C; Gray, Matthew D; Stamatatos, Leonidas; Burton, Dennis R; Koff, Wayne C; Cohen, Myron S; Haynes, Barton F; Casazza, Joseph P; Connors, Mark; Corti, Davide; Lanzavecchia, Antonio; Sattentau, Quentin J; Weiss, Robin A; West, Anthony P; Bjorkman, Pamela J; Scheid, Johannes F; Nussenzweig, Michel C; Shapiro, Lawrence; Mascola, John R; Kwong, Peter D

    2015-06-01

    The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies. PMID:26004070

  14. A dominant EV71-specific CD4+ T cell epitope is highly conserved among human enteroviruses.

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    Ruicheng Wei

    Full Text Available CD4+ T cell-mediated immunity plays a central role in determining the immunopathogenesis of viral infections. However, the role of CD4+ T cells in EV71 infection, which causes hand, foot and mouth disease (HFMD, has yet to be elucidated. We applied a sophisticated method to identify promiscuous CD4+ T cell epitopes contained within the sequence of the EV71 polyprotein. Fifteen epitopes were identified, and three of them are dominant ones. The most dominant epitope is highly conserved among enterovirus species, including HFMD-related coxsackieviruses, HFMD-unrelated echoviruses and polioviruses. Furthermore, the CD4+ T cells specific to the epitope indeed cross-reacted with the homolog of poliovirus 3 Sabin. Our findings imply that CD4+ T cell responses to poliovirus following vaccination, or to other enteroviruses to which individuals may be exposed in early childhood, may have a modulating effect on subsequent CD4+ T cell response to EV71 infection or vaccine.

  15. Methodologies for the analysis of HCV-specific CD4+ T cells

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    Megha eLokhande

    2015-02-01

    Full Text Available Virus-specific CD4+ T cells play a major role in viral infections, such as hepatitis C virus (HCV. Viral clearance is associated with vigorous and multispecific CD4+ T cell responses, while chronic infection has been shown to be associated with weak or absent T cell responses. Most of these studies have used functional assays to analyse virus-specific CD4+ T cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4+ T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analysed in detail. A novel assay, in which virus-specific CD4+ T cell frequencies can be determined by de novo CD154 (CD40 ligand expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4+ T cells will be discussed in this review.

  16. Impact of nicotine on the interplay between human periodontal ligament cells and CD4+ T cells.

    Science.gov (United States)

    Ge, Xin; Liu, Ying-Feng; Wong, Yong; Wu, Li-Zheng; Tan, Ling; Liu, Fen; Wang, Xiao-Jing

    2016-09-01

    Periodontitis is a common infectious disease associated with destruction of periodontal ligaments and alveolar bones. CD4(+) T cell-mediated immune response is involved in the progression of periodontitis. Tobacco consumption increases the risk of periodontal disease. However, the impact of nicotine on the interaction between human periodontal ligament (PDL) cells and CD4(+) T cells remains unrevealed. Our study aims to investigate the effect of nicotine on PDL cells and the cocultured CD4(+) T cells. The PDL cell cultures were established by explants from healthy individuals, exposed to nicotine or α-bungarotoxin (α-BTX), and incubated solely or in combination with CD4(+) T cells. Afterwards, cell viability, secreted cytokines, and matrix metalloproteinases (MMPs) were evaluated. In monoculture of PDL cells, nicotine dramatically repressed cell viability and increased apoptosis. Meanwhile, α-BTX largely reversed the nicotine-induced apoptosis and increased viability of PDL cells. Compared with the monoculture, MMP-1, MMP-3, interleukin (IL)-1β, IL-6, IL-17, and IL-21 in supernatant of cocultures were markedly elevated after treatment with nicotine. Moreover, α-BTX significantly attenuated nicotine-triggered production of these components either in mono- or co-cultures. In addition, PDL cell-derived CXCL12 following nicotine treatment recruited CD4(+) T cells. Above all, nicotine deteriorated periodontitis partially by promoting PDL cell-CD4(+) T cell-mediated inflammatory response and matrix degradation. PMID:26553320

  17. Restrictions to HIV-1 replication in resting CD4+T lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Xiaoyu Pan; Hanna-Mari Baldauf; Oliver T Keppler; Oliver T Fackler

    2013-01-01

    CD4+ T lymphocytes represent the main target cell population of human immunodeficiency virus (HIV).In an activated state,CD4+ T cells residing in lymphoid organs are a major reservoir of ongoing HIV-1 replication in infected individuals.In contrast,resting CD4+ T cells are highly resistant to productive HIV-1 infection,yet are massively depleted during disease progression and represent a substantial latent reservoir for the virus in vivo.Barriers preventing replication of HIV-1 in resting CD4+ T cells include a rigid layer of cortical actin and,early after HIV-1entry,a block that limits reverse transcription of incoming viral RNA genomes.Defining the molecular bases of these restrictions has remained one of the central open questions in HIV research.Recent advances unraveled mechanisms by which HIV-1 bypasses the entry block and established the host cell restriction factor SAMHD1,a deoxynucleoside triphosphate triphosphohydrolase,as a central determinant of the cellular restriction to HIV-1 reverse transcription in resting CD4+ T cells.This review summarizes our current molecular and pathophysiological understanding of the multi-faceted interactions of HIV-1 with resting CD4+ T lymphocytes.

  18. TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis.

    Science.gov (United States)

    Lu, Ning; Wang, Yi-Hong; Wang, Yui-Hsi; Arima, Kazuhiko; Hanabuchi, Shino; Liu, Yong-Jun

    2009-09-28

    Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4(+) T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4(+) T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4(+) T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4(+) T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4(+) T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4(+) T cell homeostasis. PMID:19770269

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

    Directory of Open Access Journals (Sweden)

    Mitra Azadniv

    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.

  20. Lymphoid tissue inducer cells: pivotal cells in the evolution of CD4 immunity and tolerance?

    Directory of Open Access Journals (Sweden)

    Peter John Lane

    2012-02-01

    Full Text Available Phylogeny suggests that the evolution of placentation in mammals was accompanied by substantial changes in the mammalian immune system: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi are members of an emerging family of innate lymphoid cells (ILCs that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3-dependent regulatory T cells (Tregs that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the Tregs that under normal circumstances are absolutely required to regulate CD4 effector cells.

  1. IL-17-Expressing CD4+ and CD8+ T Lymphocytes in Human Toxoplasmosis

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    Jéssica Líver Alves Silva

    2014-01-01

    Full Text Available This study aimed to measure the synthesis of Th1 and Th2 cytokines by mononuclear cells after culture with live T. gondii and identified Th17 (CD4+ and Tc17 (CD8+ cells in toxoplasma-seronegative and toxoplasma-seropositive parturient and nonpregnant women. Cytometric bead arrays were used to measure cytokine levels (IL-2, TNF-α, IFN-γ, IL-4, IL-5, and IL-10; immunophenotyping was used to characterize Th17 and Tc17 cells, and the cells were stained with antibodies against CD4+ and CD8+ T cells expressing IL-17. The addition of tachyzoites to cell cultures induced the synthesis of IL-5, IL-10, and TNF-α by cells from seronegative parturient women and of IL-5 and IL-10 by cells from seropositive, nonpregnant women. We observed a lower level of IL-17-expressing CD4+ and CD8+ T lymphocytes in cultures of cells from seronegative and seropositive parturient and nonpregnant women that were stimulated with tachyzoites, whereas analysis of the CD4+ and CD8+ T cell populations showed a higher level of CD4+ T cells compared with CD8+ T cells. These results suggest that the cytokine pattern and IL-17-expressing CD4+ and CD8+ T lymphocytes may have important roles in the inflammatory response to T. gondii, thus contributing to the maintenance of pregnancy and control of parasite invasion and replication.

  2. Cervical Cancer

    Science.gov (United States)

    ... to see your doctor. www.cdc.gov/cancer/knowledge 1-800-CDC-INFO Are there tests that can prevent cervical cancer or find it early? There are two tests that can either help prevent cervical cancer or find it early: • The Pap test (or Pap smear)looks for precancers, cell changes, on the cervix ...

  3. Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection

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    John Thornhill

    2014-11-01

    Full Text Available Introduction: Despite normalization of total CD4 counts, ongoing immune dysfunction is noted amongst those on antiretroviral therapy (ART. Low CD4/CD8 ratio is associated with a high risk of AIDS and non-AIDS events and may act as a marker of immune senescence [1]. This ratio is improved by ART although normalization is uncommon (~7% [2]. The probability of normalization of CD4 count is improved with immediate ART initiation in primary HIV infection (PHI [3]. We examined whether CD4/CD8 ratio similarly normalized in immediate vs. deferred ART at PHI. Material and Methods: Using data from the SPARTAC trial and the UK Register of HIV Seroconverters, we examined the effect of ART with time (continuous from HIV seroconversion (SC on CD4/CD8 ratio (≥1 adjusted for sex, risk group, ethnicity, enrolment from an African site and both CD4 count and age at ART initiation. We also examined that effect by dichotomizing HIV duration at ART initiation (ART started within six months of SC: early ART; ART initiated>six months after SC: deferred. We also considered time to CD4 count normalization (≥900 cells/mm3. Results: In total, 353 initiated ART with median (IQR 97.9 (60.5, 384.5 days from estimated seroconversion; 253/353 early ART, 100 deferred ART. At one year after starting ART, 114/253 (45% early ART had normalized CD4/8 ratio, compared with 11/99 (11% in the deferred group, whilst 83/253 (33% of early ART had normalized CD4 counts, compared with 3/99 (3% in the deferred group. Individuals initiating within six months of PHI were significantly more likely to reach normal ratio than those initiating later (HR, 95% CI 2.96, 1.75 – 5.01, p<0.001. The longer after SC ART was initiated, the reduced likelihood of achieving normalization of CD4/CD8 ratio (HR 0.98, 95% CI 0.96 – 0.99 for each 30-day increase. CD4 count at ART initiation was also associated with normalization, as expected (HR 1.002, 95% CI 1.001 – 1.002, p<0.001. There was an

  4. Detection of CD4+/CD8+T Lymphocyte Ratio and CD4+CD25+ Treg in Peripheral Blood of Patients with Sporadic Vitiligo%散发型白癜风患者外周血CD4+/CD8+T细胞比值及CD4+CD25+T细胞的检测

    Institute of Scientific and Technical Information of China (English)

    叶蓉; 马刚; 胡小平; 彭曦

    2012-01-01

    目的 检测散发型白癜风患者外周血CD4+/CD8+T细胞比值及CD4+CD25+调节性T细胞水平,探讨其与散发型白癜风发病的关系.方法 散发型白癜风患者29例,男13例,女16例.通过流式细胞仪对散发型白癜风患者外周血CD4+/CD8+T细胞比值及CD4+CD25+调节性T细胞水平进行检测,并与20例健康人相比较.结果 与健康对照组相比,散发型白癜风患者外周血中CD4+/CD8+T细胞比值的差异无统计学意义(P>0.05),而CD4+CD25+调节性T细胞水平明显减少,差异有统计学意义(P<0.05),但在不同病程的患者中CD4+CD25+调节性T细胞数量的差异无统计学意义(P>0.05).结论 散发型白癜风患者外周血中存在CD4+CD25+调节性T细胞水平下降,可能与散发型白癜风的发生发展有一定关系.%Objective To detect the CD4+/CD8+ T lymphocyte ratio and the CD4+CD25+ Treg level in peripheral blood of patients with sporadic vitiligo, and to investigate its role in the pathogenesis of sporadic vitiligo. Methods Peripheral blood samples were taken from 29 outpatients with sporadic vitiligo, including 13 males and 16 females. The CD4+/CD8+ T lymphocyte ratio and the CD4+CD25+ Treg level was detected in peripheral blood of patients with sporadic vitiligo by flow cytometry, as well as controlled samples from 20 healthy human. Results There was no difference on the ratio of CD4+/CD8+ T lymphocyte between the patients with sporadic vitiligo and healthy people (P>0.05). Compared to the controlled group, the proportion of CD4+CD25+ Treg was significantly lower in sporadic vitiligo patients(P0.05). Conclusion The level of CD4+CD25+ Treg is lower in peripheral blood of sporadic vitiligo patients, which might play a role in the pathogenesis and development of sporadic vitiligo.

  5. Correlation between viral load, plasma levels of CD4 - CD8 T lymphocytes and AIDS-related oral diseases: a multicentre study on 30 HIV+ children in the HAART era.

    Science.gov (United States)

    Nesti, M; Carli, E; Giaquinto, C; Rampon, O; Nastasio, S; Giuca, M R

    2012-01-01

    This experimental retrospective multicenter study carried out on 30 seropositive children treated with Highly Active Antiretroviral Therapy (HAART), between the ages of 18 months and 14 years, in the clinical categories Centers for Disease Control (CDC) classification 1993 A (mildly symptomatic), B (moderately symptomatic) and C (severely symptomatic) aims to: 1) clinically and immunologically demonstrate the therapeutic benefits of HAART; 2) monitor the frequency of AIDS-related oral diseases in seropositive children with HAART therapy; 3) monitor the plasma levels of total CD4, CD4 percent, CD8 percent, CD4-CD8 lymphocytes and viral load from 1997 to 30 April, 2011. The statistic methods used are the analysis of covariance and the Bonferroni Test. More than 100 AIDS-related oral diseases were found in the study samples, the most frequent being: oral candidiasis, oropharyngeal candidiasis, HSV-1 herpetic esophagyitis, herpetic gingivolstomatitis (RHOG), recurrent aphthous stomatitis (RAS), parotid swelling, oral hairy leukoplakia (OHL), Herpes simplex 1 (HSV-1), linear gingival erythema (LGE), necrotizing gingivitis (NUG), facial lipodistrophy, facial-cervical lymphadenopathy (FCL), xerostomia, dysgeusia, hyposmia, oral mucosa hyperpigmentation (OMP). The Bonferroni test showed a significant difference between the mean plasma values (mpVTL) of total CD4, CD4 percentage, CD4-CD8 T lymphocytes and Viral Load (VL) of the various oral diseases found in the study samples. The therapeutic benefits of HAART are: immune reconstitution; reduction of the HIV/AIDS-related stomatology diseases; prevention and cure of the AIDS correlated neoplasias; reduction in maternal-fetal transmission of the HIV virus. The negative effects of HAART in relation to odontostomatolgy are: increase in oral lesions from HPV; xerostomia; dysgeusia/ageusia, hyposmia, perioral paresthesia; hyperpigmentation of oral mucosa; facial lipodystrophy, recurrent aphthous stomatitis (RAS). No case of

  6. Human CD4-major histocompatibility complex class II (DQw6) transgenic mice in an endogenous CD4/CD8-deficient background: reconstitution of phenotype and human-restricted function

    OpenAIRE

    1994-01-01

    To reconstitute the human immune system in mice, transgenic mice expressing human CD4 and human major histocompatibility complex (MHC) class II (DQw6) molecules in an endogenous CD4- and CD8-deficient background (mCD4/8-/-), after homologous recombination, have been generated. We report that expression of human CD4 molecule in mCD4/8-/- mice rescues thymocyte development and completely restores the T cell compartment in peripheral lymphoid organs. Upon vesicular stomatitis virus (VSV) challen...

  7. CELLULAR AND POPULATION PLASTICITY OF HELPER CD4 T CELL RESPONSES

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    Gesham eMagombedze

    2013-08-01

    Full Text Available Vertebrates are constantly exposed to pathogens, and the adaptive immunity has most likely evolved to control and clear such infectious agents. CD4 T cells are the major players in the adaptive immune response to pathogens. Following recognition of pathogen-derived antigens naïve CD4 T cells differentiate into effectors which then control pathogen replication either directly by killing pathogen-infected cells or by assisting with generation of cytotoxic T lymphocytes or pathogen-specific antibodies. Pathogen-specific effector CD4 T cells are highly heterogeneous in terms of cytokines they produce. Three major subtypes of effector CD4 T cells have been identified: T-helper 1 (Th1 cells producing IFN-g and TNF-α, Th2 cells producing IL-4 and IL-10, and Th17 cells producing IL-17. How this heterogeneity is maintained and what regulates changes in effector T cell composition during chronic infections remains poorly understood. In this review we discuss recent advances in our understanding of CD4 T cell differentiation in response to microbial infections. We propose that a change in the phenotype of pathogen-specific effector CD4 T cells during chronic infections, for example, from Th1 to Th2 response as observed in Mycobacteriumavium ssp. paratuberculosis (MAP infection of ruminants, can be achieved by conversion of T cells from one effector subset to another (cellular plasticity or due to differences in kinetics (differentiation, proliferation, death of different effector T cell subsets (population plasticity. We also shortly review mathematical models aimed at describing CD4 T cell differentiation and outline areas for future experimental and theoretical research.

  8. Quorum sensing in CD4+ T cell homeostasis: a hypothesis and a model.

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    Afonso R.M. Almeida

    2012-05-01

    Full Text Available Homeostasis of lymphocyte numbers is believed to be due to competition between cellular populations for a common niche of restricted size, defined by the combination of interactions and trophic factors required for cell survival. Here we propose a new mechanism: homeostasis of lymphocyte numbers could also be achieved by the ability of lymphocytes to perceive the density of their own populations. Such a mechanism would be reminiscent of the primordial quorum sensing systems used by bacteria, in which some bacteria sense the accumulation of bacterial metabolites secreted by other elements of the population, allowing them to count the number of cells present and adapt their growth accordingly. We propose that homeostasis of CD4+ T cell numbers may occur via a quorum-sensing-like mechanism, where IL-2 is produced by activated CD4+ T cells and sensed by a population of CD4+ Treg cells that expresses the high-affinity IL-2Rα-chain and can regulate the number of activated IL-2-producing CD4+ T cells and the total CD4+T cell population. In other words, CD4+ T cell populations can restrain their growth by monitoring the number of activated cells, thus preventing uncontrolled lymphocyte proliferation during immune responses. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled T cell activation and autoimmunity. Finally, we present a mathematical model that describes the role of IL-2 and quorum-sensing mechanisms in CD4+ T cell homeostasis during an immune response.

  9. Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

    DEFF Research Database (Denmark)

    Engsig, Frederik N; Zangerle, Robert; Katsarou, Olga;

    2014-01-01

    BACKGROUND: Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after 3 years...... start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality. RESULTS: Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/µL after 3 years of...

  10. Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia

    OpenAIRE

    Johnson, Susan; Eller, Michael; Teigler, Jeffrey E.; Maloveste, Sebastien M.; Schultz, Bruce T.; Soghoian, Damien Z.; Lu, Richard; Oster, Alexander F.; Chenine, Agnès-Laurence; Alter, Galit; Dittmer, Ulf; Marovich, Mary; Merlin L Robb; Michael, Nelson L.; Bolton, Diane

    2015-01-01

    CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcri...

  11. Clinical syndrome in HIV/AIDS resulting in hospitalization based on the CD4 count

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    Mahmood Mahmood

    2009-01-01

    Full Text Available (Received 3 November, 2009 ; Accepted 10 March, 2010AbstractBackground and purpose: The CD4 lymphocyte count is the strongest index indicating the severity of immunodeficiency, prediction of incidence, diagnosis, and making a decision to start anti retroviral treatment and follow up of therapeutic response. This study was conducted to establish the clinical syndrome resulting in admission of patients with HIV infection based on the CD4 count.Materials and methods: This cross-sectional descriptive study was performed on 71 HIV patients admitted at least for onece to Imam Khomeini Hospital, Tehran during 2008 and 2009. HIV infection was confirmed by positive ELISA and Western blot. The obtained data were analyzed using SPSS software, version 16.Results: From a total of 71 patients, 8.5% were female and 91.5% were male. The mean age of the subjects was 35 ± 8.1 years. 74.6% were addicted and 38% had a prison history. The average CD4 count was 202.9 ± 20.09 /ML. 21.1% of the patients received anti-retroviral medication. 49.3% of HIV patients had hepatitis C and 18.6% had hepatitis B simultaneously. Patient with PCP, toxoplasma and TB had the least CD4 count, with an average of 75.85, 94.66 and 143.95 /ML respectively. Patients with empyema, esophagititis and abscess of femur had the highest CD4 average count of 698, 536 and 349.5 ML, respectively. There was a significant correlation between pneumonia and CD4<200/ML (P=0.001 and also, between prison history and TB (P<0.001, and between TB and CD4<200/ML (P=0.012.Conclusion: The prevalence of Pneumocystic pneumonia, Toxoplasmosis and TB syndrome may be higher in patients with CD4<200/ML and the incidence of pulmonary TB were greater in patients eith prison history. Key words: HIV, AIDS, CD4 lymphocyte count, pneumonia, tuberclosisJ Mazand Univ Med Sci 2009; 19(74: 70-77 (Persian.

  12. Access to CD4 Testing for Rural HIV Patients: Findings from a Cohort Study in Zimbabwe.

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    Florian Vogt

    Full Text Available CD4 cell count measurement remains an important diagnostic tool for HIV care in developing countries. Insufficient laboratory capacity in rural Sub-Saharan Africa is frequently mentioned but data on the impact at an individual patient level are lacking. Urban-rural discrepancies in CD4 testing have not been quantified to date. Such evidence is crucial for public health planning and to justify new yet more expensive diagnostic procedures that could circumvent access constraints in rural areas.To compare CD4 testing among rural and urban HIV patients during the first year of treatment.Records from 2,145 HIV positive adult patients from a Médecins sans Frontières (Doctors without Borders HIV project in Beitbridge, Zimbabwe, during 2011 and 2012 were used for a retrospective cohort analysis. Covariate-adjusted risk ratios were calculated to estimate the effects of area of residence on CD4 testing at treatment initiation, six and 12 months among rural and urban patients.While the proportion of HIV patients returning for medical consultations at six and 12 months decreased at a similar rate in both patient groups, CD4 testing during consultations dropped to 21% and 8% for urban, and 2% and 1% for rural patients at six and 12 months, respectively. Risk ratios for missing CD4 testing were 0.8 (95% CI 0.7-0.9, 9.2 (95% CI 5.5-15.3, and 7.6 (95% 3.7-17.1 comparing rural versus urban patients at treatment initiation, six and 12 months, respectively.CD4 testing was low overall, and particularly poor in rural patients. Difficulties with specimen transportation were probably a major factor underlying this difference and requires new diagnostic approaches. Our findings point to severe health system constraints in providing CD4 testing overall that need to be addressed if effective monitoring of HIV patients is to be achieved, whether by alternative CD4 diagnostics or newly-recommended routine viral load testing.

  13. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

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    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.

  14. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help.

    Science.gov (United States)

    Iijima, Norifumi; Iwasaki, Akiko

    2016-05-26

    Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood-brain barrier and blood-nerve barrier, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-γ and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread. PMID:27225131

  15. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

    Science.gov (United States)

    Doitsh, Gilad; Galloway, Nicole L. K.; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

    2014-01-01

    The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of `anti-AIDS' therapeutics targeting the host rather than the virus.

  16. 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.

  17. IL-21-producer CD4+ T cell kinetics during primary simian immunodeficiency virus infection.

    Science.gov (United States)

    Shi, Shoi; Seki, Sayuri; Matano, Tetsuro; Yamamoto, Hiroyuki

    2013-01-01

    IL-21 signaling is important for T cell and B cell-mediated clearance of chronic viral infections. While non-cognate follicular helper CD4+ T cells (TFH) are indicated to be pivotal in providing IL-21-mediated help to activated B cells within germinal centers, how this signaling may be disrupted in early AIDS virus infection is not clear. In this study, we assessed the lineage and kinetics of peripheral blood IL-21-producing CD4+ T cells in primary simian immunodeficiency virus (SIV) infection of rhesus macaques. After SIV challenge, antigen-nonspecific IL-21 production was observed in Th1, Th2 and Th17 cells with Th1 dominance. While IL-21+ Th2 and IL-21+ Th17 showed variable kinetics, an increase in total IL-21+ CD4+ T cells and IL-21+ Th1 from week 3 to week 8 was observed, preceding plasma SIV-specific IgG development from week 5 to week 12. SIV Gag-specific IL-21+ CD4+ T cells detectable at week 2 were decreased in frequencies at week 5. Results imply that kinetics of IL-21+ CD4+ T cells comprised of multiple lineages, potentially targeted by SIV with a bias of existing frequencies during their precursor stage, associate with availability of cooperative B-cell help provided through a proportionate precursor pool developing into TFH and subsequent anti-SIV antibody responses. PMID:23791954

  18. World Health Organization guidelines should not change the CD4 count threshold for antiretroviral therapy initiation

    Directory of Open Access Journals (Sweden)

    Nathan Geffen

    2013-03-01

    Full Text Available The World Health Organization (WHO currently recommends that HIV-positive adults start antiretroviral therapy (ART at CD4 counts <350 cells/μl. Several countries have changed their guidelines to recommend ART irrespective of CD4 count or at a threshold of 500 CD4 cells/μl. Consequently, WHO is currently revising its treatment guidelines and considering recommending ART initiation at CD4 counts <500 cells/μl. Such decisions are critically important, as WHO guidelines inform healthcare policies in developing countries and are used by activists in their advocacy work. Changing the CD4 initiation point from 350 to 500 cells/μl would, however, be premature and have profound cost implications on Global Fund, President’s Emergency Plan for AIDS Relief (PEPFAR and developing country health budgets. We should be willing to campaign for such a change in guidelines despite cost implications, if supported by evidence. However, the evidence remains outstanding. S Afr J HIV Med 2013;14(1:6-7. DOI:10.7196/SAJHIVMED.906

  19. Dissecting How CD4 T Cells Are Lost During HIV Infection.

    Science.gov (United States)

    Doitsh, Gilad; Greene, Warner C

    2016-03-01

    Although the replicative life cycle of HIV within CD4 T cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4 T cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis. PMID:26962940

  20. Role of distinct CD4(+) T helper subset in pathogenesis of oral lichen planus.

    Science.gov (United States)

    Wang, Hui; Zhang, Dunfang; Han, Qi; Zhao, Xin; Zeng, Xin; Xu, Yi; Sun, Zheng; Chen, Qianming

    2016-07-01

    Oral lichen planus (OLP) is one of the most common chronic inflammatory oral mucosal diseases with T-cell-mediated immune pathogenesis. In subepithelial and lamina propria of OLP local lesions, the presence of CD4(+) T helper (CD4(+) Th) cells appeared as the major lymphocytes. These CD4(+) T lymphocytes can differentiate into distinct Th cell types such as Th1, Th2, Treg, Th17, Th22, Th9, and Tfh within the context of certain cytokines environment. Growing evidence indicated that Th1/Th2 imbalance may greatly participate into the cytokine network of OLP immunopathology. In addition, Th1/Th2 imbalance can be regulated by the Treg subset and also greatly influenced by the emerging novel CD4(+) Th subset Th17. Furthermore, the presence of novel subsets Th22, Th9 and Tfh in OLP patients is yet to be clarified. All these Th subsets and their specific cytokines may play a critical role in determining the character, extent and duration of immune responses in OLP pathogenesis. Therefore, we review the roles of distinct CD4(+) Th subsets and their signature cytokines in determining disease severity and susceptibility of OLP and also reveal the novel therapeutic strategies based on T lymphocytes subsets in OLP treatment. PMID:26693958

  1. Specific interaction of aurintricarboxylic acid with the human immunodeficiency virus/CD4 cell receptor

    International Nuclear Information System (INIS)

    The triphenylmethane derivative aurintricarboxylic acid (ATA), but not aurin, selectively prevented the binding of OKT4A/Leu-3a monoclonal antibody (mAb) and, to a lesser extent, OKT4 mAb to the CD4 cell receptor for human immunodeficiency virus type 1 (HIV-1). The effect was seen within 1 min at an ATA concentration of 10 μM in various T4+ cells (MT-4, U-937, peripheral blood lymphocytes, and monocytes). It was dose-dependent and reversible. ATA prevented the attachment of radiolabeled HIV-1 particles to MT-4 cells, which could be expected as the result of its specific binding to the HIV/CD4 receptor. Other HIV inhibitors such as suramin, fuchsin acid, azidothymidine, dextran sulfate, heparin, and pentosan polysulfate did not affect OKT4A/Leu-3a mAb binding to the CD4 receptor, although the sulfated polysaccharides suppressed HIV-1 adsorption to the cells at concentrations required for complete protection against HIV-1 cytopathogenicity. Thus, ATA is a selective marker molecule for the CD4 receptor. ATA also interfered with the staining of membrane-associated HIV-1 glycoprotein gp120 by a mAb against it. These unusual properties of a small molecule of nonimmunological origin may have important implications for the study of CD4/HIV/AIDS pathogenesis and possibly treatment

  2. Effects of BCG-polysaccharide nucleic acid on CD4+IL-17+ T cells and CD4+Foxp3+ Treg in asthmatic rats%卡介苗多糖核酸对哮喘大鼠CD4+IL-17+T细胞与CD4+Foxp3+调节性T细胞的影响

    Institute of Scientific and Technical Information of China (English)

    涂玲; 梁颖红; 魏明; 刘佳; 龚艳杰; 张俊华; 张宜花

    2015-01-01

    目的 观察卡介苗多糖核酸(BCG-PSN)对哮喘大鼠支气管肺泡灌洗液(BALF)、外周血和淋巴液中CD4+IL-17+T细胞(CD4+IL-17+T)与CD4+Foxp3+调节性T细胞(CD4+Foxp3+ Treg)百分比及IL-10、IL-17水平的影响及其可能机制.方法 SD大鼠60只随机分为对照组(n=15)、哮喘组(n=15)、BCG-PSN干预对照组(n=15)和BCG-PSN干预哮喘组(n=15).哮喘组和BCG-PSN干预哮喘组使用卵白蛋白建立大鼠哮喘模型,对照组和BCG-PSN干预对照组以等量生理盐水代替卵白蛋白,BCG-PSN干预哮喘组和BCG-PSN干预对照组均使用BCG-PSN进行干预.收集各组大鼠BALF、外周血和淋巴液,采用流式细胞术检测CD4+IL-17+T和CD4+Foxp3+ Treg百分比,酶联免疫吸附法(ELISA)检测IL-10和IL-17水平.结果 各组大鼠淋巴液中CD4+Foxp3+ Treg百分比、IL-10水平较BALF和外周血均明显升高(均P<0.01),CD4+IL-17+T百分比、IL-17水平较BALF和外周血均明显下降(均P<0.01).哮喘组大鼠BALF、淋巴液和外周血CD4+Foxp3+ Treg百分比、IL-10水平较其余3组均显著降低,而CD4+IL-17+T百分比、IL-17水平较其余3组均显著升高(均P<0.01).BCG-PSN干预哮喘组大鼠BALF、淋巴液和外周血CD4+Foxp3+ Treg百分比和IL-10水平较哮喘组显著升高(均P<0.01),与对照组和BCG-PSN干预对照组比较差异无统计学意义(均P>0.05).BCG-PSN干预哮喘组大鼠BALF、淋巴液和外周血CD4+IL-17+T细胞百分比、IL-17水平较哮喘组均显著下降(均P<0.01),与对照组和BCG-PSN干预对照组比较差异无统计学意义(P>0.05).结论 BCG-PSN可能通过调节哮喘大鼠外周血和淋巴液中CD4+Foxp3+ Treg和CD4+IL-17+T的百分比及相关细胞因子水平,改善机体免疫功能,从而减轻哮喘的炎性反应.%Objective To investigate the effect of BCG-polysaccharide nucleic acid (BCG-PSN) on the levels of CD4+IL-17+ T cells and CD4+Foxp3+ regulatory T cells(Treg),interleukin-10 (IL-10) and IL-17 in bronchoalveolar

  3. Cervical spondylosis

    Science.gov (United States)

    ... Past neck injury (often several years before) Past spine surgery Ruptured or slipped disk Severe arthritis Small fractures ... Kshettry VR. Cervical spondylosis. In: Benzel EC, ed. Spine Surgery . 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:chap ...

  4. Cervical Cancer

    Science.gov (United States)

    ... 162 KB) This information in Spanish (en español) Female reproductive system Select image to view larger Related ... D., FACS, Captain, U.S. Public Health Service Medical Director, National Breast and Cervical Cancer Early Detection Program, ...

  5. Cervical Stenosis

    Science.gov (United States)

    ... Accumulation of pus in the uterus is called pyometra. Symptoms Before menopause, cervical stenosis may cause menstrual ... present but not cause symptoms. A hematometra or pyometra can cause pain or cause the uterus to ...

  6. IL-33 enhances retinoic acid signaling on CD4+ T cells.

    Science.gov (United States)

    Gajardo, Tania; Pérez, Francisco; Terraza, Claudia; Campos-Mora, Mauricio; Noelle, Randolph J; Pino-Lagos, Karina

    2016-09-01

    Several molecules have been described as CD4+ T cells differentiation modulators and among them retinoic acid (RA) and more recently, IL-33, have been studied. Due to the similarities in T helper cell skewing properties between RA and IL-33, we asked whether IL-33 intersects, directly or indirectly, the RA signaling pathway. Total CD4+ T cells from DR5-luciferase mice were activated in the presence of RA with or without IL-33, and RA signaling was visualized using ex vivo imaging. Our results demonstrate that IL-33 itself is able to trigger RA signaling on CD4+ T cells, which is highly increased when IL-33 is added in conjunction with RA. This study presents IL-33 as a potential player that may synergize with RA in controlling T cell differentiation, and suggests that IL-33 may be an attractive target in controlling T cell differentiation in vivo. PMID:27322964

  7. CD4+ T Cell Depletion in Human Immunodeficiency Virus (HIV Infection: Role of Apoptosis

    Directory of Open Access Journals (Sweden)

    Angelita Rebollo

    2011-05-01

    Full Text Available Human immunodeficiency virus (HIV infection is principally a mucosal disease and the gastrointestinal (GI tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis.

  8. CD4+ T Cell Depletion in Human Immunodeficiency Virus (HIV) Infection: Role of Apoptosis

    Science.gov (United States)

    Février, Michèle; Dorgham, Karim; Rebollo, Angelita

    2011-01-01

    Human immunodeficiency virus (HIV) infection is principally a mucosal disease and the gastrointestinal (GI) tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT) might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis. PMID:21994747

  9. Rapid and sustained CD4(+) T-cell-independent immunity from adenovirus-encoded vaccine antigens

    DEFF Research Database (Denmark)

    Holst, Peter J; Bartholdy, Christina; Buus, Anette Stryhn;

    2007-01-01

    absence of CD4(+) T-cell help were sustained in the long term and able to expand and control a secondary challenge with LCMV. Our results demonstrate that modifications to the antigen used in adenovirus vaccines may be used to improve the induced T-cell response. Such a strategy for CD4(+) T-cell...... elicited with an adenovirus-encoded minimal epitope covalently linked to beta(2)-microglobulin. We demonstrate that the beta(2)-microglobulin-linked epitope induced an accelerated and augmented CD8(+) T-cell response. Furthermore, the immunity conferred by vaccination with beta(2)-microglobulin......-linked lymphocytic choriomeningitis virus (LCMV)-derived epitopes was long-lived and protective. Notably, in contrast to full-length protein, the response elicited with the beta(2)-microglobulin-linked LCMV-derived epitope was CD4(+) T-cell independent. Furthermore, virus-specific CD8(+) T cells primed in the...

  10. Analisis perilaku dinamik pada sel T CD4+ dan sel T CD8+ terhadap infeksi mikobakterium

    Directory of Open Access Journals (Sweden)

    Alfi Nur Rochmatin

    2014-05-01

    Full Text Available Model matematika pada infeksi mikobakterium tuberkulosis yang berbentuk sistem persamaan diferensial nonlinear orde satu. Penelitian ini telah mengkonstruksi model matematika pada interaksi makrofag, sel T CD4+ dan sel T CD8+ dengan pengaruh usia. Solusi numerik pada model matematika ini dengan menggunakan ODE 45 berbantuan matlab. Analisis kestabilan diamati melalui titik tetap dengan mencari matriks jacobian dan nilai eigen dari titik tetap tersebut, maka dapat diperoleh bahwa semua titik tetap tersebut tidak stabil. Berdasarkan analisis perilaku dinamik pada sel T CD4+ dan sel T CD8+pada usia muda dan usia tua maka akan diperoleh bahwa sel T CD4+dan sel T CD8+ lebih banyak mempengaruhi populasi bakteri mikobakterium tuberkulosis dari pada saat usia muda

  11. CD4(+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis.

    Directory of Open Access Journals (Sweden)

    Jamie C Zampell

    Full Text Available INTRODUCTION: Lymphedema is a chronic disorder that occurs commonly after lymph node removal for cancer treatment and is characterized by swelling, fibrosis, inflammation, and adipose deposition. Although previous histological studies have investigated inflammatory changes that occur in lymphedema, the precise cellular make up of the inflammatory infiltrate remains unknown. It is also unclear if this inflammatory response plays a causal role in the pathology of lymphedema. The purpose of this study was therefore to characterize the inflammatory response to lymphatic stasis and determine if these responses are necessary for the pathological changes that occur in lymphedema. METHODS: We used mouse-tail lymphedema and axillary lymph node dissection (ANLD models in order to study tissue inflammatory changes. Single cell suspensions were created and analyzed using multi-color flow cytometry to identify individual cell types. We utilized antibody depletion techniques to analyze the causal role of CD4+, CD8+, and CD25+ cells in the regulation of inflammation, fibrosis, adipose deposition, and lymphangiogenesis. RESULTS: Lymphedema in the mouse-tail resulted in a mixed inflammatory cell response with significant increases in T-helper, T-regulatory, neutrophils, macrophages, and dendritic cell populations. Interestingly, we found that ALND resulted in significant increases in T-helper cells suggesting that these adaptive immune responses precede changes in macrophage and dendritic cell infiltration. In support of this we found that depletion of CD4+, but not CD8 or CD25+ cells, significantly decreased tail lymphedema, inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells significantly increased lymphangiogenesis both in our tail model and also in an inflammatory lymphangiogenesis model. CONCLUSIONS: Lymphedema and lymphatic stasis result in CD4+ cell inflammation and infiltration of mature T-helper cells. Loss of CD4+ but

  12. Perforin Expression by CD4+ Regulatory T Cells Increases at Multiple Sclerosis Relapse: Sex Differences

    Directory of Open Access Journals (Sweden)

    Silvia Sánchez-Ramón

    2012-06-01

    Full Text Available Multiple sclerosis (MS represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ TReg in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (TReg within the cerebrospinal fluid (CSF takes place during MS relapse. Not previously described, the presence of CD4+ TReg in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2 and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ TReg playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ TReg in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ TReg in MS, and contributes to the understanding of MS pathophysiology.

  13. Immunosuppression of canine renal allograft recipients by CD4 and CD8 monoclonal antibodies

    International Nuclear Information System (INIS)

    A state of tolerance to MHC mismatched allografts can be generated in rodents by treatment with CD4 and CD8 monoclonal antibodies (mAb). In order to transpose this type of therapy to large animals and ultimately to the clinic, a suitable model is required. To this end we have generated a series of mAb to the canine CD4, CD8, and Thy-l antigens and have tested their ability to prevent rejection of renal allografts. Donor-recipient pairs were selected from a colony of mongrel dogs in which untreated rejection of two haplotype-mismatched kidneys occurred by day 7 (defined as a serum creatinine > 300 μmol/l). Therapy with either the CD4 or the CD8 mAb, using no other immunosuppression, did not prolong graft survival. Depletion of T cells by a Thy-l mAb prior to surgery only extended graft survival to day 9. However, treating with combinations of mAb up to day 10 (CD4 plus Thy-l; CD4 plus CD8; or CD4 plus CD8 plus Thy-l) prolonged renal allograft function up to 25 days. Combination of the triple mAb therapy with a sub-therapeutic immunosuppressive drug regimen (cyclosporin A plus azathioprine that alone gave a median survival of 15 days) favored survival to a median of 38 days. This protocol also inhibited the antiglobulin response that had curtailed the effects of mAb treatment, opening the way to more extended, and potentially tolerizing, mAb plus drug regimens. (au) (23 refs.)

  14. Immunosuppression of canine renal allograft recipients by CD4 and CD8 monoclonal antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Watson, C.J.E.; Davies, H.S.; Rebello, P.R.U.B.; McNair, R.; Rasmussen, A.; Calne, R.Y.; Metcalfe, S.M. (Department of Surgery, University of Cambridge (United Kingdom)); Cobbold, S.P.; Thiru, S.; Waldmann, H. (Department of Pathology, University of Cambridge (United Kingdom))

    1994-01-01

    A state of tolerance to MHC mismatched allografts can be generated in rodents by treatment with CD4 and CD8 monoclonal antibodies (mAb). In order to transpose this type of therapy to large animals and ultimately to the clinic, a suitable model is required. To this end we have generated a series of mAb to the canine CD4, CD8, and Thy-l antigens and have tested their ability to prevent rejection of renal allografts. Donor-recipient pairs were selected from a colony of mongrel dogs in which untreated rejection of two haplotype-mismatched kidneys occurred by day 7 (defined as a serum creatinine > 300 [mu]mol/l). Therapy with either the CD4 or the CD8 mAb, using no other immunosuppression, did not prolong graft survival. Depletion of T cells by a Thy-l mAb prior to surgery only extended graft survival to day 9. However, treating with combinations of mAb up to day 10 (CD4 plus Thy-l; CD4 plus CD8; or CD4 plus CD8 plus Thy-l) prolonged renal allograft function up to 25 days. Combination of the triple mAb therapy with a sub-therapeutic immunosuppressive drug regimen (cyclosporin A plus azathioprine that alone gave a median survival of 15 days) favored survival to a median of 38 days. This protocol also inhibited the antiglobulin response that had curtailed the effects of mAb treatment, opening the way to more extended, and potentially tolerizing, mAb plus drug regimens. (au) (23 refs.).

  15. The absolute lymphocyte count accurately estimates CD4 counts in HIV-infected adults with virologic suppression and immune reconstitution

    Directory of Open Access Journals (Sweden)

    Barnaby Young

    2014-11-01

    Full Text Available Introduction: The clinical value of monitoring CD4 counts in immune reconstituted, virologically suppressed HIV-infected patients is limited. We investigated if absolute lymphocyte counts (ALC from an automated blood counting machine could accurately estimate CD4 counts. Materials and Methods: CD4 counts, ALC and HIV viral load (VL were extracted from an electronic laboratory database for all patients in HIV care at the Communicable Diseases Centre, Tan Tock Seng Hospital, Singapore (2008–13. Virologic suppression was defined as consecutive HIV VLs 300 cells/mm3. CD4 counts were estimated using the CD4% from the first value >300 and an ALC 181–540 days later. Results: A total of 1215 periods of virologic suppression were identified from 1183 patients, with 2227 paired CD4-ALCs available for analysis. 98.3% of CD4 estimates were within 50% of the actual value. 83.3% within 25% and 40.5% within 10%. The error pattern was approximately symmetrically distributed around a mean of −6.5%, but significant peaked and with mild positive skew (kurtosis 4.45, skewness 1.07. Causes for these errors were explored. Variability between lymphocyte counts measured by ALC and flow cytometry did not follow an apparent pattern, and contributed to 32% of the total error (median absolute error 5.5%, IQR 2.6–9.3. The CD4% estimate was significantly lower than the actual value (t-test, p<0.0001. The magnitude of this difference was greater for lower values, and above 25%, there was no significant difference. Precision of the CD4 estimate was similar as baseline CD4% increased, however accuracy improved significantly: from a median 16% underestimation to 0% as baseline CD4% increased from 12 to 30. Above a CD4% baseline of 25, estimates of CD4 were within 25% of the actual value 90.2% of the time with a median 2% underestimation. A robust (bisqaure linear regression model was developed to correct for the rise in CD4% with time, when baseline was 14–24

  16. Downregulation of IL-12 and a novel negative feedback system mediated by CD25+CD4+ T cells

    International Nuclear Information System (INIS)

    CD25+CD4+ regulatory T cells suppress immune responses and are believed to play roles in preventing autoimmune diseases. However, the mechanism(s) underlying the suppression and the regulation of their homeostasis remain to be elucidated. Here we show that these regulatory T cells downregulated CD25-CD4+ T-cell-mediated production of IL-12 from antigen-presenting cells, which can act as a growth factor for CD25-CD4+ T cells. We further found that CD25+CD4+ T cells, despite their well-documented 'anergic' nature, proliferate significantly in vitro only when CD25-CD4+ T cells are present. Notably, this proliferation was strongly dependent on IL-2 and relatively independent of IL-12. Thus, CD25+CD4+ T cells suppress CD25-CD4+ T-cell responses, at least in part, by inhibiting IL-12 production while they themselves can undergo proliferation with the mediation of CD25-CD4+ T cells in vitro. These results offer a novel negative feedback system involving a tripartite interaction among CD25+CD4+ and CD25-CD4+ T cells, and APCs that may contribute to the termination of immune responses

  17. Soluble human CD4 elicits an antibody response in rhesus monkeys that inhibits simian immunodeficiency virus replication

    International Nuclear Information System (INIS)

    Rhesus monkeys infected with the simian immunodeficiency virus of macaques (SIVmac) demonstrate significant virologic and clinical improvement as a result of treatment with human recombinant soluble CD4 (rsCD4). The authors show that human rsCD4 does not efficiently inhibit SIVmac replication in bone marrow macrophages of rhesus monkeys and does not significantly augment bone marrow hematopoietic colony formation in vitro. However, plasma of human rsCD4-treated rhesus monkeys does exhibit significant anti-SIVmac activity in vitro. Plasma of these animals efficiently blocks SIVmac replicaton in peripheral blood lymphocytes and bone marrow macrophages. It also increases granulocyte/macrophage colony formation in vitro by bone marrow cells of SIVmac-infected monkeys. This plasma and the IgG fraction of plasma from a rhesus monkey immunized with human rsCD4 in adjuvant demonstrate reactivity with a soluble form of the rhesus monkey CD4 molecule, exhibit binding to CD4+ but not CD8+ concanavalin A-activated rhesus monkey peripheral blood lymphocytes, and precipitate the CD4 molecule from surface-labeled activated rhesus monkey peripheral blood lymphocytes. Moreover, anti-viral activity is demonstrable in the IgG fraction of plasma from a human rsCD4-immunized monkey. These studies raise the possibility that a modified human CD4 molecule serving as an immunogen might elicit an antibody response that could potentially induce a beneficial therapeutic response in human immunodeficiency virus-infected individuals

  18. Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Yiyuan; Wang, Xin Xiang; Mariuzza, Roy A [Maryland

    2012-07-11

    Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ~65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.

  19. Detection of resistance mutations and CD4 slopes in individuals experiencing sustained virological failure

    DEFF Research Database (Denmark)

    Schultze, Anna; Paredes, Roger; Sabin, Caroline;

    2014-01-01

    INTRODUCTION: Several resistance mutations have been shown to affect viral fitness, and the presence of certain mutations might result in clinical benefit for patients kept on a virologically failing regimen due to an exhaustion of drug options. We sought to quantify the effect of resistance...... mutations on CD4 slopes in patients undergoing episodes of viral failure. MATERIALS AND METHODS: Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test...

  20. CD26 + CD4 + T cell counts and attack risk in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Ross, C; Koch-Henriksen, Nils;

    2005-01-01

    patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta....... CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in...

  1. Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro✩

    OpenAIRE

    Secor, Eric R.; Singh, Anurag; Guernsey, Linda A.; McNamara, Jeff T.; Zhan, Lijun; Maulik, Nilanjana; Thrall, Roger S.

    2009-01-01

    Bromelain (Br), an extract from pineapple stem with cysteine protease activity, exerts anti-inflammatory effects in a number of inflammatory models. We have previously shown that Br treatment decreased activated CD4+ T cells and has a therapeutic role in an ovalbumin-induced murine model of allergic airway disease. The current study was designed to determine the effect of Br on CD4+ T cell activation, specifically the expression of CD25 in vitro. CD25 is up regulated upon T cell activation, f...

  2. 3D QSAR Study on Alpha Keto Amide Derivatives as gp120-CD4 Inhibitors

    Directory of Open Access Journals (Sweden)

    Vinayak D. More

    2012-01-01

    Full Text Available The present communication deals with 3D QDAR analysis on series of Alpha keto amide derivatives some for the designing of new GP120-CD4 inhibitors with anti HIV activity. The four different QSAR models are generated using data set of 32 molecules as gp120-CD4 inhibitors from literature studies. The 3D QSAR result gives insights for understanding of the relationship between structural features of substituted alpha keto amide derivatives and their activities which should be useful to design newer potential anti-HIV agents.

  3. Patterns of CD4+ T-lymphocytes and liver enzymes in adult HIV seropositive cases

    OpenAIRE

    Saheed O. Usman; Ganiyu B. Agboola; Nafisat O. Akintayo-Usman; Ibiwumi N. Isola; Florence C. Umeozulu; Patrick O Osho; Mattew T. Oluwole

    2015-01-01

    Objectives: HIV/AIDS is a rapidly growing epidemic in sub-Saharan Africa, in particular Nigeria. HIV is a retrovirus that primarily infects components of the human immune system such as CD4+ T-cells, macrophages and dendritic cells. This study is therefore designed to evaluate the CD4+ T-cell count and liver enzymes of adult HIV seropositive subjects receiving Highly Active Antiretroviral Therapy (HAART) and those yet to be started on HAART as well as HIV seronegative control subjects. Me...

  4. Low dose antigen promotes induction of FOXP3 in human CD4+ T cells

    OpenAIRE

    Long, S. Alice; Rieck, Mary; Tatum, Megan; Bollyky, Paul L.; Wu, Rebecca P.; Muller, Isabelle; Ho, Jhon-Chun; Shilling, Heather G.; Buckner, Jane H.

    2011-01-01

    Low antigen dose promotes induction and persistence of Treg in mice, yet few studies have addressed the role of antigen dose in the induction of adaptive CD4+FOXP3+ Treg in humans. To this end, we examined the level of FOXP3 expression in human CD4+CD25− T cells upon activation with autologous antigen presenting cells and varying doses of peptide. Antigen specific T cells expressing FOXP3 were identified by flow cytometry using MHC Class II tetramer (Tmr). We found an inverse relationship bet...

  5. Role of CD4+ and CD8+ T cells in murine resistance to street rabies virus.

    OpenAIRE

    Perry, L. L.; Lodmell, D L

    1991-01-01

    Mice of the SJL/J and BALB/cByJ inbred strains are naturally resistant to street rabies virus (SRV) injected via the intraperitoneal route. To determine the cellular mechanism of resistance, monoclonal antibodies specific for CD4+ or CD8+ subsets of T cells were used to deplete the respective cell population in SRV-infected animals. Elimination of CD4+ T-helper cells abrogated the production of immunoglobulin G (IgG) neutralizing antibodies in response to rabies virus infection and reversed t...

  6. IL-17-Expressing CD4 + and CD8 + T Lymphocytes in Human Toxoplasmosis

    OpenAIRE

    Jéssica Líver Alves Silva; Karine Rezende-Oliveira; Marcos Vinicius da Silva; César Gómez-Hernández; Bethânea Crema Peghini; Neide Maria Silva; José Roberto Mineo; Virmondes Rodrigues Júnior

    2014-01-01

    This study aimed to measure the synthesis of Th1 and Th2 cytokines by mononuclear cells after culture with live T. gondii and identified Th17 (CD4+) and Tc17 (CD8+) cells in toxoplasma-seronegative and toxoplasma-seropositive parturient and nonpregnant women. Cytometric bead arrays were used to measure cytokine levels (IL-2, TNF-α, IFN-γ, IL-4, IL-5, and IL-10); immunophenotyping was used to characterize Th17 and Tc17 cells, and the cells were stained with antibodies against CD4+ and CD8+ T c...

  7. Multiple in vitro and in vivo regulatory effects of budesonide in CD4+ T lymphocyte subpopulations of allergic asthmatics.

    Directory of Open Access Journals (Sweden)

    Elisabetta Pace

    Full Text Available BACKGROUND: Increased activation and increased survival of T lymphocytes characterise bronchial asthma. OBJECTIVES: In this study the effect of budesonide on T cell survival, on inducible co-stimulator T cells (ICOS, on Foxp3 and on IL-10 molecules in T lymphocyte sub-populations was assessed. METHODS: Cell survival (by annexin V binding and ICOS in total lymphocytes, in CD4+/CD25+ and in CD4+/CD25- and Foxp3 and IL-10 in CD4+/CD25+ and in CD4+/CD25-cells was evaluated, by cytofluorimetric analysis, in mild intermittent asthmatics (n = 19 and in controls (n = 15. Allergen induced T lymphocyte proliferation and the in vivo effects of budesonide in mild persistent asthmatics (n = 6 were also explored. RESULTS: Foxp3 was reduced in CD4+/CD25- and in CD4+/CD25+ cells and ICOS was reduced in CD4+/CD25+ cells but it was increased in CD4+CD25-in asthmatics when compared to controls. In asthmatics, in vitro, budesonide was able to: 1 increase annexin V binding and to reduce ICOS in total lymphocytes; 2 increase annexin V binding and Foxp3 and to reduce ICOS in CD4+/CD25- cells; 3 reduce annexin V binding and to increase IL-10 and ICOS in CD4+/CD25+ cells; 4 reduce cell allergen induced proliferation. In vivo, budesonide increased ICOS in CD4+/CD25+ while it increased Foxp3 and IL-10 in CD4+/CD25+ and in CD4+/CD25- cells. CONCLUSIONS: Budesonide modulates T cell survival, ICOS, Foxp3 and IL-10 molecules differently in T lymphocyte sub-populations. The findings provided shed light on new mechanisms by which corticosteroids, drugs widely used for the clinical management of bronchial asthma, control T lymphocyte activation.

  8. General Information about Cervical Cancer

    Science.gov (United States)

    ... Research Cervical Cancer Treatment (PDQ®)–Patient Version General Information About Cervical Cancer Key Points Cervical cancer is ... the NCI website . Cervical Cancer During Pregnancy General Information About Cervical Cancer During Pregnancy Treatment of cervical ...

  9. Expression of regulatory CD4+CD25+ Treg,CD4+CD25higTreg cells and Foxp3 mRNA in wheezing infants and its clinical significance%CD4+CD25+、CD4+CD25hig调节性T细胞和Foxp3mRNA在婴幼儿喘息中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    彭力; 钟礼立; 黄寒; 厉娟; 梁沫; 李云

    2012-01-01

    Objective To evaluate the changes of CD4+ CD25+ Treg,CD4 +CD25hig Treg and Foxp3 mRNA in peripheral blood from wheezing infantsMethods Fifty-one wheezing infants and twenty healthy volunteers were included in this study. The proportion of CD4 + CD25 + Treg and CD4 + CD25hig Treg population in total T cells was evaluated by flow cytometric analysis. The expression of Foxp3 mRNA was tested by flow cytometry. Total serum IgE of wheezy infants was detected by enzyme immunoassay. Results Compared with those of healthy control, the frequency of CD4 + CD25 + Treg and CD4 + CD25hig Treg in the peripheral blood from wheezing infants showed a significant increase (6. 31 + 2. 96) % / (3.52 + 1.46) % ,P<0. 01 ,P<0. 01, respectively).The expression of CD4 + CD25+ Treg,CD4 + CD25hig Treg and Foxp3 mRNA in peripheral blood from wheezing infants with atopy burden was lower than those from non-wheezing infants(P<0. 05). The correlation analysis showed that CD4 + CD25hig Treg (r= -0. 75 , P<0.01) and Foxp3 mRNA(r= -0. 61,P<0. 01) had significantly positive relation with total serum IgE,while CD4+CD25 + Treg had significantly negative relation with total serum IgE(r=0. 36,P<0. 05). Conclusion CD4+CD25+ Treg, CD4+CD25hig Treg and Foxp3 mRNA play an important role in activation of wheezing infants.%目的 探讨婴幼儿喘息CD4+CD25+、CD4+CD25hig调节性T细胞(Treg)和叉头/翼状螺旋转录因子(Foxp3)mRNA的表达及意义.方法 采用流式细胞术检测51例首次喘息婴幼儿外周血CD4+CD25+Treg和CD4+CD25higTreg的比例,RT-PCR检测Foxp3 mRNA的表达量,酶联免疫吸附法(ELASA)检测总IgE水平,并与正常婴幼儿对照.结果 喘息婴幼儿外周血CD4+CD25+Treg、CD4+CD25higTreg占CD4+T细胞的百分比分别为(6.31+2.96)%和(3.52+1.46)%,均明显低于健康对照组(P<0.01);特应征喘息组CD4+CD25+Treg、CD4+CD25higTreg及Foxp3 mRNA表达均低于非特应征喘息组(P<0.05).喘息患儿CD4+CD25higTreg百分率及Foxp3 mRNA表达与

  10. CD4+CD25+调节性T细胞对哮喘大鼠免疫功能影响%Effect of CD4+CD25+Regulatory T Cells on the Immunologic Function in Rats with Asthma

    Institute of Scientific and Technical Information of China (English)

    薛克营; 金卫国; 王成国; 程立; 杨中卫; 王正艳

    2009-01-01

    目的:观察CD4+CD25+调节性T细胞(CD4+CD25+Treg)对CD4+CD25-T细胞增殖和Th1/Th2细胞因子分泌的影响,探讨其在哮喘气道炎症中的作用机制.方法:将哮喘大鼠CD4+CD25-T细胞分别与卵白蛋白(OVA)免疫耐受大鼠CD4+Cd25+Treg细胞和哮喘大鼠CD4+CD25+Treg细胞联合培养,3H胸腺嘧啶核苷(3H-TdR)掺入法测量细胞增殖情况,ELISA检测细胞IL-4、IL-5和IFN-γ含量.结果:OVA耐受大鼠CD4+CD25+Treg细胞能抑制CD4+CD25-T细胞增殖和Th2细胞因子分泌(P<0.05);哮喘大鼠CD4+CD25+Treg细胞可明显抑制IFN-γ的分泌(P<0.05).结论:OVA免疫耐受大鼠CD4+CD25+Treg细胞可能通过抑制哮喘大鼠CD4+CD25-T细胞增殖和影响Th1/Th2平衡发挥作用,哮喘大鼠CD4+CD25+Treg细胞存在功能异常,可能与哮喘的发病有关.

  11. Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation.

    Science.gov (United States)

    Li, Jasmine; Hardy, Kristine; Phetsouphanh, Chan; Tu, Wen Juan; Sutcliffe, Elissa L; McCuaig, Robert; Sutton, Christopher R; Zafar, Anjum; Munier, C Mee Ling; Zaunders, John J; Xu, Yin; Theodoratos, Angelo; Tan, Abel; Lim, Pek Siew; Knaute, Tobias; Masch, Antonia; Zerweck, Johannes; Brezar, Vedran; Milburn, Peter J; Dunn, Jenny; Casarotto, Marco G; Turner, Stephen J; Seddiki, Nabila; Kelleher, Anthony D; Rao, Sudha

    2016-06-15

    Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4(+) T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4(+) T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells. PMID:27149922

  12. Cryptococcal rib osteomyelitis as primary and only symptom of idiopathic CD4 penia

    DEFF Research Database (Denmark)

    Legarth, Rebecca A; Christensen, Merete; Calum, Henrik;

    2014-01-01

    A 59-year old man with idiopathic CD4 lymphopenia presented with extensive disseminated Cryptococcus neoformans infection including a large rib cryptoccocoma, vertebral spondylitis and pleural empyema. Complete resection of the affected part of the rib was necessary after failure of initial antif...

  13. Imaging rheumatoid arthritis specifically with technetium99m CD4-specific (T-helper lymphocytes) antibodies

    International Nuclear Information System (INIS)

    CD4 expressing T-lymphocytes are involved in the pathogenesis of rheumatoid arthritis, so the possibility of using radiolabelled CD4-specific antibodies to localise diseased joints was studied. Prospectively six patients with rheumatoid arthritis were investigated in all. Five of them received 200-300 μg of a 555 MBq technetium 99m CD4-specific antibody (MAX.16H5) and were examined with three phase bone scans. Max.16H5 (IgG1) was labelled according to the mercaptoethanol (Schwarz) method. Lumphocytes of one patient were isolated on a Ficoll-Hypaque gradient and labelled with the antibody in vitro. Scans were performed 1.5 h, 4 and 24 h post injection in anterior and posterior views. In all patients, diseased joints could be clearly imaged at as early as 1.5 h. The localisation of the diseased joints correlated (P0.05). According to these data we conclude that 99mTc-labelled CD4-specific antibodies specifically image actively diseased joints in rheumatoid arthritis. (orig.)

  14. Idiopathic CD4(+) T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

    NARCIS (Netherlands)

    T.W. Kuijpers; H. IJspeert; E.M.M. van Leeuwen; M.H. Jansen; M.D. Hazenberg; K.C. Weijer; R.A.W. van Lier; M. van der Burg

    2011-01-01

    A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4(+) T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimm

  15. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

    NARCIS (Netherlands)

    T.W. Kuijpers (Taco W.); H. IJspeert (Hanna); E.M.M. van Leeuwen (Ester); M.H. Jansen (Machiel H.); M.D. Hazenberg (Mette D.); K. Weijer (Kees); R.A.W. Van Lier (Rene A. W.); M. van der Burg (Mirjam)

    2011-01-01

    textabstractA girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, o

  16. HIV-1 gp120 induces NFAT nuclear translocation in resting CD4+ T-cells

    International Nuclear Information System (INIS)

    The replication of human immunodeficiency virus (HIV) in CD4+ T-cells is strongly dependent upon the state of activation of infected cells. Infection of sub-optimally activated cells is believed to play a critical role in both the transmission of virus and the persistence of CD4+ T-cell reservoirs. There is accumulating evidence that HIV can modulate signal-transduction pathways in a manner that may facilitate replication in such cells. We previously demonstrated that HIV gp120 induces virus replication in resting CD4+ T cells isolated from HIV-infected individuals. Here, we show that in resting CD4+ T-cells, gp120 activates NFATs and induces their translocation into the nucleus. The HIV LTR encodes NFAT recognition sites, and NFATs may play a critical role in promoting viral replication in sub-optimally activated cells. These observations provide insight into a potential mechanism by which HIV is able to establish infection in resting cells, which may have implications for both transmission of HIV and the persistence of viral reservoirs

  17. Human CD4+ T cells require exogenous cystine for glutathione and DNA synthesis

    DEFF Research Database (Denmark)

    Levring, Trine B; Kongsbak-Wismann, Martin; Rode, Anna Kathrine Obelitz;

    2015-01-01

    aim of this study was to elucidate why activated human T cells require exogenous Cys2 in order to proliferate. We activated purified naïve human CD4+ T cells and found that glutathione (GSH) levels and DNA synthesis were dependent on Cys2 and increased in parallel with increasing concentrations of Cys...

  18. The effects of intermittent, CD4-guided antiretroviral therapy on body composition and metabolic parameters

    NARCIS (Netherlands)

    E. Martinez; F. Visnegarwala; B. Grund; A. Thomas; C. Gibert; J. Shlay; F. Drummond; D. Pearce; S. Edwards; P. Reiss; W. El-Sadr; A. Carr

    2010-01-01

    Objective: To assess the effects of decreased antiretroviral therapy exposure on body fat and metabolic parameters. Design: Substudy of the Strategies for Management of Anti-Retroviral Therapy study, in which participants were randomized to intermittent CD4-guided [Drug Conservation (DC) group] or t

  19. On-chip sample preparation by controlled release of antibodies for simple CD4 counting

    NARCIS (Netherlands)

    Beck, M.; Brockhuis, S.; Velde, van der N.; Breukers, C.; Greve, J.; Terstappen, L.W.M.M.

    2012-01-01

    We present a simple system for CD4 and CD8 counting for point-of-care HIV staging in low-resource settings. Automatic sample preparation is achieved through a dried reagent coating inside a thin (26 μm) counting chamber, allowing the delayed release of fluorochrome conjugated monoclonal antibodies a

  20. CD4+ T Lymphocytes count in sickle cell anaemia patients attending a tertiary hospital

    Directory of Open Access Journals (Sweden)

    Omotola Toyin Ojo

    2014-01-01

    Full Text Available Background: Sickle cell haemoglobin (HbS is the commonest abnormal haemoglobin and it has a worldwide distribution. Reports have shown that patients with sickle cell anaemia (HbSS have an increased susceptibility to infection leading to increased morbidity and mortality. Impaired leucocyte function and loss of both humoral and cell-mediated immunity are some of the mechanisms that have been reported to account for the immunocompromised state in patients with sickle cell disease. This study was carried out to determine the CD4+ T lymphocytes count in patients with sickle cell anaemia. Materials and Methods: A comparative cross-sectional study of 40 sickle cell anaemia patients in steady state (asymptomatic for at least 4 weeks attending haematology clinic and 40 age and sex-matched healthy HbA control were recruited into the study. Both HbS patients and the controls were HIV negative. The blood samples obtained were analyzed for CD4+ T cell by Flow cytometry. Results: The study found that there was no significant difference in the number of CD4+ T lymphocyte count between individuals with sickle cell anaemia and HbA (1016 ± 513 cells/μL vs 920 ± 364cells/μL. Conclusion: It is recommended that the functionality of CD4+ T lymphocyte should be considered rather than the number in further attempt to elucidate the cellular immune dysfunction in patients with sickle cell anaemia.

  1. PREVALENCE OF PULMONARY TUBERCULOSIS IN HIV POSITIVE INDIVIDUALS AND ITS ASSOCIATION WITH CD 4 COUNT

    OpenAIRE

    Sudha; Meena; Atul R.; Kurhade

    2015-01-01

    PURPOSE: There is grave concern regarding increase in HIV associated Tuberculosis (TB) and emergence of Multi Drug Resistant (MDR) and Extremely Drug Resistant (XDR) TB. It is essential to know prevalence of TB in HIV patients and its association with CD 4 count. MATERIAL & METHODS: A total of 362 patients were screened for Pulmonary ...

  2. People living with HIV infection / AIDS - A study on lymph node FNAC and CD4 count

    Directory of Open Access Journals (Sweden)

    Shobhana A

    2002-01-01

    Full Text Available Between July 1997 and December 2000, 1616 HIV seropositive persons were identified by Western Blot test at the School of Tropical Medicine, Kolkata. Four hundred seventy two (29.2% of them had generalized lymphadenopathy. CD4 count could be done in only 54 of these 472 subjects (11.4%. These 54 patients, consisting of 40 males (74% and 14 females (26% were the subjects of the study. Their mean age was 29.5 years. In all these subjects, FNAC was done from the enlarged lymph nodes (non-inguinal. Reactive hyperplasia was seen in 30 cases (55.5% whose absolute CD4 count varied between 411-945 cells/µL (median value 670 cells/µL. Evidence of tuberculous lymphadenitis was detected in 22 (41% with CD4 counts varying between 113 and 422 cells/µL (median value 212 cells/µL. Non-Hodgkin lymphoma was diagnosed in 2 cases (3.7% with CD4 count 79-113 cells/µL. All patients had evidence of HIV-1 infection, excepting one case of dual infection (HIV-1 and 2.

  3. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad; Issazadeh-Navikas, Shohreh; Goertsches, Robert; Martin, Roland; Comabella, Manuel

    OBJECTIVE: To evaluate whether T cells expressing CCR5 and CXCR3 from multiple sclerosis (MS) patients are more resistant to apoptosis. METHODS: Expression of CD69, TNF-R1, Fas, FasL, bcl-2, and bax was investigated in 41 MS patients and 12 healthy controls by flow cytometry in CD4+ and CD8+ T ce...

  4. Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions

    DEFF Research Database (Denmark)

    Jönsson, Peter; Southcombe, Jennifer H; Santos, Ana Mafalda;

    2016-01-01

    value is two to three orders of magnitude higher than previously measured 2D Kd values for interacting leukocyte surface proteins. Calculations indicated, however, that CD4/pMHC II binding would increase rates of T-cell receptor (TCR) complex phosphorylation by threefold via the recruitment of Lck, with...

  5. Memory IL-22-producing CD4+ T cells specific for Candida albicans are present in humans.

    Science.gov (United States)

    Liu, Yun; Yang, Binyan; Zhou, Maohua; Li, Li; Zhou, Hui; Zhang, Jianping; Chen, Hui; Wu, Changyou

    2009-06-01

    Co-expression of IL-22 and IL-17 has been identified and demonstrated to be involved in the immunopathogenesis of some autoimmune diseases as well as the defense against pathogenic infections in animal studies. However, the properties of IL-22-producing cells in humans remain largely unclear. In the present study, we showed that IL-22 could be induced from human PBMC following various polyclonal stimulations. The majority of IL-22-producing cells in PBMC were CD4(+) T cells with a memory cell phenotype. In addition, we found that a subset of IL-22(+) T cells produced IL-22 alone, whereas other IL-22(+) T cells co-expressed cytokines typical of Th1, Th2 and Th17 cells. Importantly, stimulation of PBMC from healthy adults with heat-inactivated Candida albicans (C. albicans) yeast or hyphae resulted in IL-22 production by central and effector memory CD4(+) T cells. Moreover, CD4(+)CCR6(+) but not CD4(+)CCR6(-) T cells produced IL-22 when stimulated with either C. albicans or PMA and ionomycin. In addition, PBMC from the individuals infected with C. albicans produced a significantly higher amount of IL-22 compared with healthy controls following stimulation with C. albicans. These data demonstrate that IL-22-producing T cells in humans may play an important role in the defense against fungal infections such as C. albicans. PMID:19449309

  6. The relationship between skin manifestations and CD4 counts among hiv positive patients

    International Nuclear Information System (INIS)

    Skin manifestations are common clinical features among HIV positive patients. The aim of this study was to document skin manifestations and their relationships with CD4 cell counts among HIV positive patients in Sanandaj. This was a descriptive study. The patients were examined for skin disorders by a dermatologist and CD4 counts were obtained from the patient's medical records. Independent samples T test were used for data analysis. In this study 66 (94.3%) patients had at least one skin problem. Fungal infections were the most common cause. The eight most common types of mucocutaneous problems were gingivitis, pallor, itching, photosensitivity, seborrheic dermatitis, candidiasis, folliculitis and tinea versicolor. The most common manifestation was gingivitis. Mean CD4 cell counts were lower in individuals with viral and bacterial skin diseases (P <0.05). The results of this study indicated that skin problems were common among HIV positive patients. Patients with advanced stages of skin disorders had relatively lower CD4 counts. Therefore examination of skin is recommended for all HIV positive patients for early detection of skin disorders, as early diagnosis and management of dermatologic problems will improve the quality of life in HIV positive patients. (author)

  7. CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection.

    Science.gov (United States)

    Espinosa, J; Herr, F; Tharp, G; Bosinger, S; Song, M; Farris, A B; George, R; Cheeseman, J; Stempora, L; Townsend, R; Durrbach, A; Kirk, A D

    2016-04-01

    Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy. PMID:26603381

  8. Relationship between CD4 count and quality of life over time among HIV patients in Uganda: a cohort study

    OpenAIRE

    Mwesigire, DM; Martin, F.; Seeley, J; Katamba, A

    2015-01-01

    Background Immunological markers (CD4 count) are used in developing countries to decide on initiation of antiretroviral therapy and monitor HIV/AIDS disease progression. HIV is an incurable chronic illness, making quality of life paramount. The direct relationship between quality of life and CD4 count is unclear. The purpose of this study is to determine the relationship between change in CD4 count and quality of life measures in a Ugandan cohort of people living with HIV. Methods ...

  9. Separation and Amplification of CD4 + CD25 + Regulatory T Cells from Sensitized Mice%致敏小鼠CD4+CD25+调节性T细胞磁珠分选及体外扩增

    Institute of Scientific and Technical Information of China (English)

    潘莉; 翁文骏; 许吕宏; 魏菁; 方建培

    2012-01-01

    The aim of this study was to separate and amplify CD4 + CD25 + Treg cells from splenocytes of sensitized nrice. The percentage of CD4 + CD25 + Treg cells was detected by flow cytometty in sensitized and normal control mice. CD4 + T, CD4 + CD25 + Treg and CD4' CD25" T cells were isolated from mouse splenocytes by MACS. CD4 + CD25+ Treg cells were expanded in vitro cultures in addition of CD3/CD28 MACSiBead and IL-2. The activity of cells was detected with 0.4% trypan blue staining. The purity of cells after sorting, the main surface marker and the level of Foxp3 were detected by flow cytometry. The results showed that CD4 + CD25 + Treg cell proportion was higher in sensitized mice than normal control mice ( P 0.05). It is concluded that the sorting of CD4 + CD25 + Treg cells is isolated successfully by MACS without affecting the vitality of target cells. The amplification of CD4 + CD25 + Treg cells is successral in vitro. Expression of surface markers and Faxp3 gene does not obviously change after amplification, so that to establish a practical method to recover and enlarge the amount of CD4 + CD25 + Treg cells in good condition.%本研究探讨致敏小鼠CD4+ CD25+调节性T细胞的分选及体外扩增.流式细胞术检测致敏小鼠及正常小鼠体内CD4+ CD25+ Treg细胞水平,免疫磁珠分选方法从小鼠脾细胞中分选出CD4+T细胞、CD4+ CD25+ Treg细胞和CD4+ CD25-T细胞,负载抗CD3/CD28单克隆抗体MACSiBead联合IL-2共同刺激CD4+ CD25+ Treg细胞进行体外扩增培养,用0.4%台盼蓝染色并计数检测细胞的活性,流式细胞术检测分选后细胞纯度、主要表面标记及Foxp3基因的表达.结果表明:致敏小鼠体内CD4+ CD25+ Treg水平较正常小鼠升高(P<0.05).分选出CD4+ CD25+Treg细胞纯度平均达到87%,细胞活性大于97%,高表达Foxp3基因.体外扩增2周后细胞数扩增倍数能够达到42倍,CD4+ CD25+ Treg细胞所占比例为85.32%,Foxp3表达由(76.92±1.72)%稍下降至(75

  10. Induction of a virus-specific effector–memory CD4+ T cell response by attenuated SIV infection

    OpenAIRE

    Gauduin, Marie-Claire; Yu, Yi; Barabasz, Amy; Carville, Angela; Piatak, Mike; Lifson, Jeffrey D.; Desrosiers, Ronald C; Johnson, R. Paul

    2006-01-01

    We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVΔnef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4–10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5–10-fold lower in frequency and inversely correlated with the level of plasma...

  11. Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis.

    Science.gov (United States)

    Hwang, SuJin; Cobb, Dustin A; Bhadra, Rajarshi; Youngblood, Ben; Khan, Imtiaz A

    2016-08-22

    CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)-susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell-intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches. PMID:27481131

  12. Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity

    OpenAIRE

    Curreli, Francesca; Kwon, Young Do; Zhang, Hongtao; Scacalossi, Daniel; Belov, Dmitry S.; Tikhonov, Artur A.; Andreev, Ivan A.; Altieri, Andrea; Kurkin, Alexander V.; Kwong, Peter D.; Debnath, Asim K.

    2015-01-01

    Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregi...

  13. Multiple In Vitro and In Vivo Regulatory Effects of Budesonide in CD4+ T Lymphocyte Subpopulations of Allergic Asthmatics

    OpenAIRE

    Elisabetta Pace; Caterina Di Sano; Stefania La Grutta; Maria Ferraro; Giuseppe Albeggiani; Giuseppe Liotta; Serena Di Vincenzo; Carina Gabriela Uasuf; Jean Bousquet; Mark Gjomarkaj

    2012-01-01

    BACKGROUND: Increased activation and increased survival of T lymphocytes characterise bronchial asthma. OBJECTIVES: In this study the effect of budesonide on T cell survival, on inducible co-stimulator T cells (ICOS), on Foxp3 and on IL-10 molecules in T lymphocyte sub-populations was assessed. METHODS: Cell survival (by annexin V binding) and ICOS in total lymphocytes, in CD4+/CD25+ and in CD4+/CD25- and Foxp3 and IL-10 in CD4+/CD25+ and in CD4+/CD25-cells was evaluated, by cytofluorimetric ...

  14. Flow Cytometric Analysis of Leishmania Reactive CD4+/CD8+ Lymphocyte Proliferation in Cutaneous Leishmaniasis

    Directory of Open Access Journals (Sweden)

    H Keshavarz

    2008-12-01

    Full Text Available Background: Determination of the division history of T cells in vitro is helpful in the study of effector mechanisms against infections. Technique described here uses the intracellular fluorescent label carboxyfluorescein diacetate succinimidyl ester (CFSE to monitor the proliferation. Methods: In a cross sectional study, blood samples were collected from 7 volunteers with history of cutaneous leishmania­sis (CL and one healthy control from endemic areas in Isfahan province who referred to the Center for Research and Training in Skin Diseases and Leprosy (CRTSDL, then CD4+/CD8+ lymphocytes and CD14+ monocytes were isolated from peri­pheral blood mononuclear cells (PBMC using mAbs and magnetic nanoparticles. CFSE labeled CD4+ or CD8+ lympho­cytes cultured with autologous monocytes in the presence of PHA, SLA, live Leishmania major or as control with­out sti­mulation. Cells were harvested after 7 days and were analyzed using flow cytometry. Results: Five consecutive divisions were monitored separately. Stimulation of CD4+ or CD8+ lymphocytes from CL sub­jects with SLA showed a significant difference in proliferation comparing with unstimulated cells (P< 0.05. The signifi­cant difference in the percentages of CD4+ cells stimulated with SLA was revealed at different divisions for each subject. In CD8+ lymphocyte, significant stronger stimulation of SLA was evident later in the proliferation process. The mean number of divisions in both CD4+/CD8+ lymphocytes stimulated with SLA was significantly greater than when stimulated with live L. major (P=0.007 / P=0.012, respectively Conclusion: The percentage of divided cells might be calculated separately in each division. The cells remained active following CFSE staining and there is possibility of functional analysis simultaneously.

  15. Human Memory CD4+ T Cell Immune Responses against Giardia lamblia.

    Science.gov (United States)

    Saghaug, Christina Skår; Sørnes, Steinar; Peirasmaki, Dimitra; Svärd, Staffan; Langeland, Nina; Hanevik, Kurt

    2016-01-01

    The intestinal protozoan parasite Giardia lamblia may cause severe prolonged diarrheal disease or pass unnoticed as an asymptomatic infection. T cells seem to play an important role in the immune response to Giardia infection, and memory responses may last years. Recently, TH17 responses have been found in three animal studies of Giardia infection. The aim of this study was to characterize the human CD4(+) T cell responses to Giardia. Peripheral blood mononuclear cells (PBMCs) were obtained from 21 returning travelers with recent or ongoing giardiasis and 12 low-risk healthy controls and stimulated in vitro with Giardia lamblia proteins. Production of tumor necrosis factor alpha (TNF-α), gamma interferon, interleukin-17A (IL-17A), IL-10, and IL-4 was measured in CD4(+) effector memory (EM) T cells after 24 h by flow cytometry. After 6 days of culture, activation and proliferation were measured by flow cytometry, while an array of inflammatory cytokine levels in supernatants were measured with multiplex assays. We found the number of IL-17A-producing CD4(+) EM T cells, as well as that of cells simultaneously producing both IL-17A and TNF-α, to be significantly elevated in the Giardia-exposed individuals after 24 h of antigen stimulation. In supernatants of PBMCs stimulated with Giardia antigens for 6 days, we found inflammation-associated cytokines, including 1L-17A, as well as CD4(+) T cell activation and proliferation, to be significantly elevated in the Giardia-exposed individuals. We conclude that symptomatic Giardia infection in humans induces a CD4(+) EM T cell response of which IL-17A production seems to be an important component. PMID:26376930

  16. Evaluation of PIMA Point-of-care CD4 Analyzer in Yunnan, China

    Directory of Open Access Journals (Sweden)

    Jun Liang

    2015-01-01

    Full Text Available Background: CD4 count is used to determine antiretroviral therapy (ART eligibility. In China, flow cytometers are mostly located in urban areas with limited access by patients residing in remote areas. In an attempt to address this issue, we conducted a study to validate the performance of Alere PIMA point-of-care CD4 analyzer. Methods: Venous and finger-prick blood specimens were collected from HIV-positive participants from two voluntary counseling and testing sites in Yunnan Province. Both venous and finger-prick blood specimens were tested with the PIMA analyzer. Venous blood specimens tested with the Becton Dickinson FACSCalibur were used as a reference. Results: Venous specimens from 396 and finger-prick specimens from 387 persons were available for analysis. CD4 counts by PIMA correlated well with those from FACSCalibur with an R2 of 0.91 for venous blood and 0.81 for finger-prick blood. Compared to FACSCalibur, the PIMA analyzer yielded lower counts with a mean bias of − 47.0 cells/μl (limit of agreement, [LOA]: −204-110 cells/μl for venous blood and −71.0 cells/μl (LOA: −295-153 cells/μl for finger-prick blood. For a CD4 threshold of 350 cells/μl, the positive predictive value (PPV of PIMA was 84.2% and 75.7% and the negative predictive value (NPV was 97.6% and 95.8% for venous and finger-prick blood, respectively. For an ART threshold of 500 cells/μl, the corresponding PPV was 90.3% and 84.0% and NPV was 94.3% and 93.4%, respectively. Conclusions: CD4 counting using venous blood with PIMA analyzers is a feasible alternative to a large flow cytometer to determine ART eligibility.

  17. CD4-independent human immunodeficiency virus infection involves participation of endocytosis and cathepsin B.

    Directory of Open Access Journals (Sweden)

    Hiroaki Yoshii

    Full Text Available During a comparison of the infectivity of mNDK, a CD4-independent human immunodeficiency virus type 1 (HIV-1 strain, to various cell lines, we found that HeLa cells were much less susceptible than 293T and TE671 cells. Hybridoma cells between HeLa and 293T cells were as susceptible as 293T cells, suggesting that cellular factors enhance the mNDK infection in 293T cells. By screening a cDNA expression library in HeLa cells, cystatin C was isolated as an enhancer of the mNDK infection. Because cathepsin B protease, a natural ligand of cystatin C, was upregulated in HeLa cells, we speculated that the high levels of cathepsin B activities were inhibitory to the CD4-independent infection and that cystatin C enhanced the infection by impairing the excessive cathepsin B activity. Consistent with this idea, pretreatment of HeLa cells with 125 µM of CA-074Me, a cathepsin B inhibitor, resulted in an 8-fold enhancement of the mNDK infectivity. Because cathepsin B is activated by low pH in acidic endosomes, we further examined the potential roles of endosomes in the CD4-independent infection. Suppression of endosome acidification or endocytosis by inhibitors or by an Eps15 dominant negative mutant reduced the infectivity of mNDK in which CD4-dependent infections were not significantly impaired. Taken together, these results suggest that endocytosis, endosomal acidification, and cathepsin B activity are involved in the CD4-independent entry of HIV-1.

  18. The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions.

    Science.gov (United States)

    Dimeloe, Sarah; Mehling, Matthias; Frick, Corina; Loeliger, Jordan; Bantug, Glenn R; Sauder, Ursula; Fischer, Marco; Belle, Réka; Develioglu, Leyla; Tay, Savaş; Langenkamp, Anja; Hess, Christoph

    2016-01-01

    Effector memory (EM) CD4(+) T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4(+) T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4(+) T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4(+) T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4(+) T cells in normoxic and hypoxic conditions. PMID:26621861

  19. Identification of two regulatory elements controlling Fucosyltransferase 7 transcription in murine CD4+ T cells.

    Science.gov (United States)

    Pink, Matthias; Ratsch, Boris A; Mardahl, Maibritt; Schröter, Micha F; Engelbert, Dirk; Triebus, Julia; Hamann, Alf; Syrbe, Uta

    2014-11-01

    Fucosyltransferase VII encoded by the gene Fut7 is essential in CD4(+) T cells for the generation of E- and P-selectin ligands (E- and P-lig) which facilitate recruitment of lymphocytes into inflamed tissues and into the skin. This study aimed to identify regulatory elements controlling the inducible Fut7 expression in CD4(+) T cells that occurs upon activation and differentiation of naive T cells into effector cells. Comparative analysis of the histone modification pattern in non-hematopoetic cells and CD4(+) T cell subsets revealed a differential histone modification pattern within the Fut7 locus including a conserved non-coding sequence (CNS) identified by cross-species conservation comparison suggesting that regulatory elements are confined to this region. Cloning of the CNS located about 500 bp upstream of the Fut7 locus, into a luciferase reporter vector elicited reporter activity after transfection of the αβ-WT T cell line, but not after transfection of primary murine CD4(+) Th1 cells. As quantification of different Fut7 transcripts revealed a predominance of transcripts lacking the first exons in primary Th1 cells we searched for an alternative promoter. Cloning of an intragenic region spanning a 1kb region upstream of exon 4 into an enhancer-containing vector indeed elicited promoter activity. Interestingly, also the CNS enhanced activity of this intragenic minimal promoter in reporter assays in primary Th1 cells suggesting that both elements interact in primary CD4(+) T cells to induce Fut7 transcription. PMID:24915132

  20. Vitamin D Actions on CD4+ T cells in Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Colleen Elizabeth Hayes

    2015-03-01

    Full Text Available This review summarizes and integrates research on vitamin D and CD4+ T lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene-environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ Treg cell and CD4+ Tr1 cell functions, and a Th1-Tr1 switch. The proposed Th1-Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell-cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, we highlight unanswered questions that potentially informative future research directions that may speed delivery of etiology-based strategies to reduce autoimmune disease.

  1. Calpain 4 is not necessary for LFA-1-mediated function in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Sarah A Wernimont

    Full Text Available BACKGROUND: T cell activation and immune synapse formation require the appropriate activation and clustering of the integrin, LFA-1. Previous work has reported that the calpain family of calcium-dependent proteases are important regulators of integrin activation and modulate T cell adhesion and migration. However, these studies have been limited by the use of calpain inhibitors, which have known off-target effects. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used a LoxP/CRE system to specifically deplete calpain 4, a small regulatory calpain subunit required for expression and activity of ubiquitously expressed calpains 1 and 2, in CD4+ T cells. CD4+ and CD8+ T cells developed normally in Capn4(F/F:CD4-CRE mice and had severely diminished expression of Calpain 1 and 2, diminished talin proteolysis and impaired casein degradation. Calpain 4-deficient T cells showed no difference in adhesion or migration on the LFA-1 ligand ICAM-1 compared to control T cells. Moreover, there was no impairment in conjugation between Capn4(F/F:CD4-CRE T cells and antigen presenting cells, and the conjugates were still capable of polarizing LFA-1, PKC-theta and actin to the immune synapse. Furthermore, T cells from Capn4(F/F:CD4-CRE mice showed normal proliferation in response to either anti-CD3/CD28 coated beads or cognate antigen-loaded splenocytes. Finally, there were no differences in the rates of apoptosis following extrinsic and intrinsic apoptotic stimuli. CONCLUSION/SIGNIFICANCE: Our findings demonstrate that calpain 4 is not necessary for LFA-1-mediated adhesion, conjugation or migration. These results challenge previous reports that implicate a central role for calpains in the regulation of T cell LFA-1 function.

  2. Human CD4+ lymphocytes for antigen quantification: characterization using conventional flow cytometry and mass cytometry.

    Science.gov (United States)

    Wang, Lili; Abbasi, Fatima; Ornatsky, Olga; Cole, Kenneth D; Misakian, Martin; Gaigalas, Adolfas K; He, Hua-Jun; Marti, Gerald E; Tanner, Scott; Stebbings, Richard

    2012-07-01

    To transform the linear fluorescence intensity scale obtained with fluorescent microspheres to an antibody bound per cell (ABC) scale, a biological cell reference material is needed. Optimally, this material should have a reproducible and tight ABC value for the expression of a known clinical reference biomarker. In this study, we characterized commercially available cryopreserved peripheral blood mononuclear cells (PBMCs) and two lyophilized PBMC preparations, Cyto-Trol and PBMC-National Institute for Biological Standard and Control (NIBSC) relative to freshly prepared PBMC and whole blood samples. It was found that the ABC values for CD4 expression on cryopreserved PBMC were consistent with those of freshly obtained PBMC and whole blood samples. By comparison, the ABC value for CD4 expression on Cyto-Trol is lower and the value on PBMC-NIBSC is much lower than those of freshly prepared cell samples using both conventional flow cytometry and CyTOF™ mass cytometry. By performing simultaneous surface and intracellular staining measurements on these two cell samples, we found that both cell membranes are mostly intact. Moreover, CD4(+) cell diameters from both lyophilized cell preparations are smaller than those of PBMC and whole blood. This could result in steric interference in antibody binding to the lyophilized cells. Further investigation of the fixation effect on the detected CD4 expression suggests that the very low ABC value obtained for CD4(+) cells from lyophilized PBMC-NIBSC is largely due to paraformaldehyde fixation; this significantly decreases available antibody binding sites. This study provides confirmation that the results obtained from the newly developed mass cytometry are directly comparable to the results from conventional flow cytometry when both methods are standardized using the same ABC approach. PMID:22539147

  3. Improving therapeutic HPV peptide-based vaccine potency by enhancing CD4+ T help and dendritic cell activation

    Directory of Open Access Journals (Sweden)

    Hung Chien-Fu

    2010-11-01

    Full Text Available Abstract Background Effective vaccination against human papillomavirus (HPV represents an opportunity to control cervical cancer. Peptide-based vaccines targeting HPV E6 and/or E7 antigens while safe, will most likely require additional strategies to enhance the vaccine potency. Methods We tested the HPV-16 E7 peptide-based vaccine in combination with a strategy to enhance CD4+ T help using a Pan HLA-DR epitope (PADRE peptide and a strategy to enhance dendritic cell activation using the toll-like receptor 3 ligand, poly(I:C. Results We observed that mice vaccinated with E7 peptide-based vaccine in combination with PADRE peptide and poly(I:C generated better E7-specific CD8+ T cell immune responses as well as significantly improved therapeutic anti-tumor effects against TC-1 tumors compared to E7 peptide-based vaccine with either PADRE peptide or poly(I:C alone. Furthermore, we found that intratumoral vaccination with the E7 peptide in conjunction with PADRE peptide and poly(I:C generates a significantly higher frequency of E7-specific CD8+ T cells as well as better survival compared to subcutaneous vaccination with the same regimen in treated mice. Conclusions The combination of PADRE peptide and poly(I:C with antigenic peptide is capable of generating potent antigen-specific CD8+ T cell immune responses and antitumor effects in vaccinated mice. Our study has significant clinical implications for peptide-based vaccination.

  4. Allo-PBSCT患者CD4+CD25+调节性T细胞的体外研究%Study on post-allogeneic peripheral blood stem cell transplantation patients'CD4 + CD25 + regulatory T cells in vitro

    Institute of Scientific and Technical Information of China (English)

    翟海龙; 赖永榕

    2011-01-01

    Objective To investigate the proliferation reaction of CD4+ CD25+ Tregs in the stimulating of costimulato-ry signal, lymphocyte reactions mixed with CD4+ CD25- T cells of CD4+ CD25+ Tregs, and cytokine secretion state of the two cells in allogeneic peripheral blood stem cell transplantation ( Allo-PBSCT) patients. Methods CD4+ CD2S+ Tregs and CD4+ CD25- T cells from peripheral blood obtained from 36 patients who had undergone Allogeneic peripheral blood stem cell transplantation (Allo-PBSCT), 7 healthy volunteers as control, were isolated with magnetic cells sorting separation. Then CD4+ CD25+ Tregs and CD4+ CD25+ Tregs + CD4+ CD25- T cells were cultered for 72 hours, stimulated by an-ti-CD3-mAbs and anti-CD28-mAbs. After that the cultures added with CCK-8 solution were incubated for 1 hour. Then OD450 were detected by ELISA. IL-10, TGF-β and IFN-γ from the two above cell cultures were detected by ELISA method. Results OD450 values of CD4+ CD25+ Tregs were both extremely lower than that of CD4+ CD25- T cells and CD4+ CD25+ Tregs + CD4+ CD25- T cells( P < 0.01). IL-10, TGF-p and IFN-γ secreted by CD4 + CD25+ Tregs in vitro from patients with and without GVHD were signigicantly lower than that of CD4+ CD25- T cells( P < 0.01 ). The 3 cytokines secreted by CD4+ CD25- Tregs + CD4+ CD25- T cells group were also signigicantly lower than that of CD4+ CD25- T cells( P <0.05 ). The cytokines secretory of Allo-PBSCT group was similar with that of control group. Conclusions If the suppressive function of CD4+ CD25+ Tregs are utilized, incidence of GVHD post- Allo-PBSCT may decrease.%目的 探讨异基因外周血干细胞移植(Allo-PBSCT)患者外周血CD4+ CD25+调节性T细胞(Tregs)在协同刺激信号作用下的增殖反应、与CD4+ CD25 -T细胞混合淋巴细胞反应及上述两种培养细胞的细胞因子分泌情况.方法 对36例Allo-PBSCT患者离体CD4+ CD25+ Tregs在抗CD3-mAbs和抗CD28-mAbs的刺激下行CD4+CD25 +Tregs培养和CD4+ CD25+ Tregs、CD4

  5. Role of CD4 molecule in the induction of interleukin 2 and interleukin 2 receptor in class II major histocompatibility complex-restricted antigen-specific T helper clones. T cell receptor/CD3 complex transmits CD4-dependent and CD4-independent signals.

    OpenAIRE

    Oyaizu, N; Chirmule, N; Pahwa, S.

    1992-01-01

    The CD4 molecule plays an essential role in antigen-induced activation of T helper (Th) cells, but its contribution to signal transduction events resulting in physiologic T cell function is ill defined. By utilizing anti-CD4 monoclonal antibodies (MAbs) that recognize distinct epitopes of CD4, we have investigated the role of CD4 molecule in antigen-induced interleukin 2 (IL-2) and IL-2 receptor (IL-2R) alpha chain expression in class II major histocompatibility complex-restricted antigen-spe...

  6. BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex-Specific Lipopeptides in Guinea Pigs.

    Science.gov (United States)

    Kaufmann, Eva; Spohr, Christina; Battenfeld, Sibylle; De Paepe, Diane; Holzhauser, Thomas; Balks, Elisabeth; Homolka, Susanne; Reiling, Norbert; Gilleron, Martine; Bastian, Max

    2016-03-15

    A new class of highly antigenic, MHC-II-restricted mycobacterial lipopeptides that are recognized by CD4-positive T lymphocytes of Mycobacterium tuberculosis-infected humans has recently been described. To investigate the relevance of this novel class of mycobacterial Ags in the context of experimental bacille Calmette-Guérin (BCG) vaccination, Ag-specific T cell responses to mycobacterial lipid and lipopeptide-enriched Ag preparations were analyzed in immunized guinea pigs. Lipid and lipopeptide preparations as well as complex Ag mixtures, such as tuberculin, mycobacterial lysates, and culture supernatants, all induced a similar level of T cell proliferation. The hypothesis that lipopeptide-specific T cells dominate the early BCG-induced T cell response was corroborated in restimulation assays by the observation that Ag-expanded T cells specifically responded to the lipopeptide preparation. A comparative analysis of the responses to Ag preparations from different mycobacterial species revealed that the antigenic lipopeptides are specific for strains of the M. tuberculosis complex. Their intriguing conservation in pathogenic tuberculous bacteria and the fact that these highly immunogenic Ags seem to be actively released during in vitro culture and intracellular infection prompt the urgent question about their role in the fine-tuned interplay between the pathogen and its mammalian host, in particular with regard to BCG vaccination strategies. PMID:26889044

  7. Specific interaction of CXCR4 with CD4 and CD8α: Functional analysis of the CD4/CXCR4 interaction in the context of HIV-1 envelope glycoprotein-mediated membrane fusion

    International Nuclear Information System (INIS)

    We investigated possible interactions between HIV-1 receptor (CD4) and the main coreceptors CXCR4 and CCR5. We found that CD4 and CXCR4 coexpressed in 293T cells form a complex that can be immunoprecipitated with antibodies directed against the extracellular domain of either protein. Mutagenesis revealed that the CD4/CXCR4 interaction maps to two previously uncharacterized basic motifs in the cytoplasmic domain of CD4. HIV-1 envelope glycoprotein-mediated membrane fusion was found to be independent of the ability of CD4 and CXCR4 to interact, whether fusion was studied in a virus-cell or a cell-cell model. However, this interaction might explain the adaptation of HIV-1 to CXCR4 as an alternative to CCR5. We found that CXCR4 also interacts with the cytoplasmic domain of CD8α in a way that is similar to the CD4/CXCR4 interaction. The CD4/CXCR4 and CD8α/CXCR4 interactions may thus be involved in cellular signaling pathways shared by the CD4 and CD8α molecules

  8. Characterisation of CD4 T cells in healthy and diseased koalas (Phascolarctos cinereus) using cell-type-specific monoclonal antibodies.

    Science.gov (United States)

    Mangar, Chandan; Armitage, Charles W; Timms, Peter; Corcoran, Lynn M; Beagley, Kenneth W

    2016-07-01

    The koala (Phascolarctos cinereus) is an arboreal herbivorous marsupial that is an Australian icon. Koalas in many parts of Australia are under multiple threats including habitat destruction, dog attacks, vehicular accidents, and infectious diseases such as Chlamydia spp. and the koala retrovirus (KoRV), which may contribute to the incidence of lymphoma and leukaemia in this species. Due to a lack of koala-specific immune reagents and assays there is currently no way to adequately analyse the immune response in healthy, diseased or vaccinated animals. This paper reports the production and characterisation of the first anti-koala CD4 monoclonal antibody (mAb). The koala CD4 gene was identified and used to develop recombinant proteins for mAb production. Fluorochrome-conjugated anti-CD4 mAb was used to measure the levels of CD4(+) lymphocytes collected from koala spleens (41.1%, range 20-45.1%) lymph nodes (36.3%, range 19-55.9%) and peripheral blood (23.8%, range 17.3-35%) by flow cytometry. Biotin-conjugated anti-CD4 mAb was used for western blot to determine an approximate size of 52 kDa for the koala CD4 molecule and used in immunohistochemistry to identify CD4(+) cells in the paracortical region and germinal centres of spleen and lymph nodes. Using the anti-CD4 mab we showed that CD4 cells from vaccinated, but not control, koalas proliferated following in vitro stimulation with UV-inactivated Chlamydia pecorum and recombinant chlamydial antigens. Since CD4(+) T cells have been shown to play a pivotal role in clearing chlamydial infection in both human and mouse infections, using this novel antibody will help determine the role CD4(+) T cells play in protection against chlamydial infection in koalas and also enhance our knowledge of how KoRV affects the koala immune system. PMID:26905635

  9. In ovo injection of anti-chicken CD25 monoclonal antibodies depletes CD4+CD25+ T cells in chickens.

    Science.gov (United States)

    Shanmugasundaram, Revathi; Selvaraj, Ramesh K

    2013-01-01

    The CD4(+)CD25(+) cells have T regulatory cell properties in chickens. This study investigated the effect of in ovo injection of anti-chicken CD25 monoclonal antibodies (0.5 mg/egg) on CD4(+)CD25(+) cell depletion and on amounts of interleukin-2 mRNA and interferon-γ mRNA in CD4(+)CD25(-) cells posthatch. Anti-chicken CD25 or PBS (control) was injected into 16-d-old embryos. Chicks hatched from eggs injected with anti-chicken CD25 antibodies had a lower CD4(+)CD25(+) cell percentage in the blood until 25 d posthatch. The anti-chicken CD25 antibody injection nearly depleted CD4(+)CD25(+) cells in the blood until 16 d posthatch. At 30 d posthatch, the CD4(+)CD25(+) cell percentage in the anti-CD25-antibody-injected group was comparable with the percentage in the control group. At 16 d posthatch, the anti-chicken CD25 antibody injection decreased CD4(+)CD25(+) cell percentages in the thymus, spleen, and cecal tonsils. Chickens hatched from anti-CD25-antibody-injected eggs had approximately 25% of CD4(+)CD25(+) cells in the cecal tonsils and thymus compared with those in the cecal tonsils and thymus of the control group. The CD4(+)CD25(-) cells from the spleen and cecal tonsils of chicks hatched from anti-chicken-CD25-injected eggs had higher amounts of interferon-γ and interleukin-2 mRNA than CD4(+)CD25(-) cells from the control group. It could be concluded that injecting anti-chicken CD25 antibodies in ovo at 16 d of incubation nearly depleted the CD4(+)CD25(+) cells until 25 d posthatch. PMID:23243240

  10. Canine CD4+CD8+ double positive T cells in peripheral blood have features of activated T cells.

    Science.gov (United States)

    Bismarck, Doris; Schütze, Nicole; Moore, Peter; Büttner, Mathias; Alber, Gottfried; Buttlar, Heiner v

    2012-10-15

    In dogs a CD4(+)CD8(+) double positive T cell subpopulation exists that has not been phenotypically defined yet. We demonstrate that canine CD4(+)CD8(+) T cells are mature CD1a(-) and TCRαβ(+) T cells. To analyse the activation potential of CD4(+)CD8(+) T cells, PBMC from dogs vaccinated against canine distemper virus (CDV) were re-stimulated with CDV. Upon antigen-specific stimulation, the CD4(+)CD8(+) T cell fraction increases and consists nearly exclusively of proliferated cells. Similarly, other features of activated effector/memory T cells such as up-regulation of CD25 and MHC-II as well as down-regulation of CD62L (L-selectin) were observed in CD4(+)CD8(+) T cells after stimulation. Canine CD4(+)CD8(+) T cells are less abundant, but more heterogeneous than porcine ones, comprising a small proportion expressing the β chain of CD8 in addition to the CD8α chain, like human CD4(+)CD8(+) T cells. In summary, this analysis provides the basis for functional characterisation of the in vivo relevance of CD4(+)CD8(+) T cells in T-cell mediated immunity. PMID:22789871

  11. Transfer of primed CD4+OX40- T lymphocytes induces increased immunity to experimental Salmonella typhimurium infections in rats

    DEFF Research Database (Denmark)

    Thygesen, P; Christensen, H B; Hougen, H P;

    1997-01-01

    The protective effect of primed CD4 T cells against a lethal dose of Salmonella typhimurium was studied in Lewis rats. Primed CD4 T cells were obtained by inoculating Lewis rats with a non-lethal dose of S. typhimurium. Four weeks after the infection, spleen non-adherent mononuclear cells were...

  12. Absolute Lymphocyte Count Is Not a Suitable Alternative to CD4 Count for Determining Initiation of Antiretroviral Therapy in Fiji

    Directory of Open Access Journals (Sweden)

    Dashika A. Balak

    2014-01-01

    Full Text Available Introduction. An absolute lymphocyte count is commonly used as an alternative to a CD4 count to determine initiation of antiretroviral therapy for HIV-infected individuals in Fiji when a CD4 count is unavailable. Methods. We conducted a retrospective analysis of laboratory results of HIV-infected individuals registered at all HIV clinics in Fiji. Results. Paired absolute lymphocyte and CD4 counts were available for 101 HIV-infected individuals, and 96% had a CD4 count of ≤500 cells/mm3. Correlation between the counts in individuals was poor (Spearman rank correlation r=0.5. No absolute lymphocyte count could be determined in this population as a suitable surrogate for a CD4 count of either 350 cells/mm3 or 500 cells/mm3. The currently used absolute lymphocyte count of ≤2300 cells/μL had a positive predictive value of 87% but a negative predictive value of only 17% for a CD4 of ≤350 cells/mm3 and if used as a surrogate for a CD4 of ≤500 cells/mm3 it would result in all HIV-infected individuals receiving ART including those not yet eligible. Weight, CD4 count, and absolute lymphocyte count increased significantly at 3 months following ART initiation. Conclusions. Our findings do not support the use of absolute lymphocyte count to determine antiretroviral therapy initiation in Fiji.

  13. CD4+ T lymphocytes injected into severe combined immunodeficient (SCID) mice lead to an inflammatory and lethal bowel disease

    DEFF Research Database (Denmark)

    Claesson, Mogens Helweg; Rudolphi, A; Kofoed, S;

    1996-01-01

    Transfer of 2 x 10(5) congenic or semiallogenic purified TCR alphabeta+ CD4+ T cells to SCID mice leads to an infiltration of the recipient gut lamina propria and epithelium with a donor-derived CD4+ T cell subset which induces a lethal inflammatory bowel disease (IBD) in the recipients. In contr...

  14. Identifying Factors Associated with Changes in CD4+ Count in HIV-Infected Adults in Saskatoon, Saskatchewan

    Directory of Open Access Journals (Sweden)

    Kelsey Hunt

    2015-01-01

    Full Text Available OBJECTIVE: To assess the impact of clinical and social factors unique to HIV-infected adults in Saskatoon, Saskatchewan, regarding the rate of CD4+ count change, and to identify factors associated with a risk of CD4+ count decline.

  15. A reliable and inexpensive EasyCD4 assay for monitoring HIV-infected individuals in resource-limited settings.

    Science.gov (United States)

    Balakrishnan, Pachamuthu; Solomon, Suniti; Mohanakrishnan, Janardhanan; Cecelia, Anitha J; Kumarasamy, Nagalingeswaran; Murugavel, Kailapuri G; Venkatakrishnan, Bhavani; Solomon, Sunil S; Crowe, Suzanne M; Ganesh, Aylur K; Thyagarajan, Sadras P; Flanigan, Timothy; Mayer, Kenneth H

    2006-09-01

    Serial measurements of absolute CD4+ T-lymphocyte counts are required to initiate and gauge response to therapy and monitor disease progression. Hence, there is an urgent need to evaluate the accuracy and validity of low-cost CD4+ T-cell count assays. Tripotassium EDTA blood specimens from HIV-infected individuals were studied using a novel flow cytometric assay (EasyCD4 assay; Guava Technologies, Hayward, CA) in comparison with standard flow cytometry (FACSCount; Becton Dickinson Immunocytometry Systems, San Jose, CA). The sensitivity, specificity value by EasyCD4 assay in enumerating absolute CD4+ T-cell counts of less than 200 cells/microL were 95% and 100%, respectively. Bland-Altman analysis showed close agreement, with the EasyCD4 assay yielding CD4+ T-cell counts a mean difference of -26 cells/microL (95% confidence interval, -96 to 44 cells/microL) higher than by flow cytometry. Our data suggest that EasyCD4 assay could be a useful alternative assay to conventional flow cytometry, may be appropriate for use in resource-limited settings. PMID:16885780

  16. Interdisciplinary Evaluation of Broadly-Reactive HLA Class II Restricted Epitopes Eliciting HIV-Specific CD4+T Cell Responses

    DEFF Research Database (Denmark)

    Buggert, M.; Norström, M.; Lundegaard, Claus; Lund, Ole; Nielsen, Morten; Karlsson, A. C.

    2011-01-01

    Background: CD4+ T cells orchestrate immune protection by ‘‘helping’’ other cells of our immune system to clear viral infections. It is well known that the preferential infection and depletion of CD4+ T cells contributes to hampered systemic T cell help following HIV infection. However, the funct...

  17. Low Baseline CD4+ Count Is Associated With Greater Bone Mineral Density Loss After Antiretroviral Therapy Initiation

    OpenAIRE

    Grant, Philip M.; Kitch, Douglas; McComsey, Grace A; Dube, Michael P.; Haubrich, Richard; Huang, Jeannie; Riddler, Sharon; Tebas, Pablo; Zolopa, Andrew R.; Collier, Ann C; Brown, Todd T.

    2013-01-01

    Low pretreatment CD4+ cell count is an independent risk factor for bone loss after antiretroviral therapy (ART) initiation, providing further evidence for the benefits of early ART. Initiation of ART at higher CD4+ counts may reduce the burden of osteoporosis and fragility fracture.

  18. Green tea epigallocatechin-3-gallate modulates differentiation of naive CD4+ T cells into specific lineage effector cells

    Science.gov (United States)

    CD4+ T helper (Th) subsets Th1, Th9, and Th17 cells are implicated in inducing autoimmunity whereas regulatory T cells (Treg) have a protective effect. We previously showed that epigallocatechin-3-gallate (EGCG) attenuated experimental autoimmune encephalomyelitis (EAE) and altered CD4+ T cell subpo...

  19. Collective excitations in liquid CD4: Neutron scattering and molecular-dynamics simulations

    Science.gov (United States)

    Guarini, E.; Bafile, U.; Barocchi, F.; Demmel, F.; Formisano, F.; Sampoli, M.; Venturi, G.

    2005-12-01

    We have investigated the dynamic structure factor S(Q,ω) of liquid CD4 at T = 97.7 K in the wave vector range 2 <= Q/nm-1 <= 15 by means of neutron scattering and molecular-dynamics simulation, in order to study the centre-of-mass collective dynamics. The agreement between the experimental spectra and those simulated using a recent ab initio based intermolecular potential is good, particularly at low Q. Underdamped collective excitations, detected in the whole experimental Q-range, characterize the dynamics of liquid CD4 as markedly different from that of other molecular liquids. Also, the energy and damping of collective excitations in methane are shown to differ considerably, even at the lowest measured Q-values, from those of linearized hydrodynamic modes. An empirical relation, able to reconcile the different wave vector ranges of mode propagation observed in disparate liquids, is investigated.

  20. Detection of circulating tumor lysate-reactive CD4+ T cells in melanoma patients

    DEFF Research Database (Denmark)

    Ladekarl, Morten; Agger, Ralf; Fleischer, Charlotte C;

    2004-01-01

    donors with high background levels of spontaneous IFN-gamma production, indicating an inhibitory effect of the lysate. CONCLUSIONS: This method for detection of a peripheral T-cell immune response in melanoma patients has several advantages for clinical use. The tumor lysate preparations may contain......PURPOSE: We wanted to study whether an allogeneic melanoma lysate would be a feasible stimulatory antigen source for detection of a peripheral CD4+ T-cell immune response in patients with medically untreated malignant melanoma. The lysate was produced from a melanoma cell line (FM3.29) which...... expresses high amounts of melanoma antigens. METHODS: Fresh peripheral blood was incubated with and without lysate for 6 h in the presence of anti-CD28/anti-CD49d MoAb (for costimulation). After flow cytometric estimation of the frequency of CD69+/IFN-gamma+ cells in the CD4+ population, the response to...

  1. Duel of the fates: the role of transcriptional circuits and noise in CD4+ cells.

    Science.gov (United States)

    Hebenstreit, Daniel; Deonarine, Andrew; Babu, M Madan; Teichmann, Sarah A

    2012-06-01

    CD4+ T cells play key roles in orchestrating adaptive immune responses, and are a popular model for mammalian cell differentiation. While immune regulation would seem to require exactly adjusted mRNA and protein expression levels of key factors, there is little evidence that this is strictly the case. Stochastic gene expression and plasticity of cell types contrast the apparent need for precision. Recent work has provided insight into the magnitude of molecular noise, as well as the relationship between noise, transcriptional circuits and epigenetic modifications in a variety of cell types. These processes and their interplay will also govern gene expression patterns in the different CD4+ cell types, and the determination of their cellular fates. PMID:22498241

  2. Interleukin-8 induces its own production in CD4+ T lymphocytes

    DEFF Research Database (Denmark)

    Gesser, B; Deleuran, Bent; Vestergård, Christian;

    1995-01-01

    The neutrophil and T cell chemotactic factor interleukin 8 (IL-8) is believed to play a pathophysiological role in the development of various inflammatory disorders. So far no other effects of IL-8 on T cells have been observed. We observed that purified CD4+ T cells in particular, but also CD8+ T...... of IL-8 mRNA expression. Further, IL-8 induced its own production in CD4+ T cells, while its synthesis by CD8+ T cells was low and not always auto-stimulatory. Both the spontaneous, as well as the IL-8 induced IL-8 production, could be inhibited in the presence of human interleukin 10 (100 ng...

  3. Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function.

    Science.gov (United States)

    Layman, Awo A K; Oliver, Paula M

    2016-05-15

    The human body is exposed to potentially pathogenic microorganisms at barrier sites such as the skin, lungs, and gastrointestinal tract. To mount an effective response against these pathogens, the immune system must recruit the right cells with effector responses that are appropriate for the task at hand. Several types of CD4(+) T cells can be recruited, including Th cells (Th1, Th2, and Th17), T follicular helper cells, and regulatory T cells. These cells help to maintain normal immune homeostasis in the face of constantly changing microbes in the environment. Because these cells differentiate from a common progenitor, the composition of their intracellular milieu of proteins changes to appropriately guide their effector function. One underappreciated process that impacts the levels and functions of effector fate-determining factors is ubiquitylation. This review details our current understanding of how ubiquitylation regulates CD4(+) T cell effector identity and function. PMID:27183634

  4. A chimeric measles virus with a lentiviral envelope replicates exclusively in CD4+/CCR5+ cells

    International Nuclear Information System (INIS)

    We generated a replicating chimeric measles virus in which the hemagglutinin and fusion surface glycoproteins were replaced with the gp160 envelope glycoprotein of simian immunodeficiency virus (SIVmac239). Based on a previously cloned live-attenuated Schwarz vaccine strain of measles virus (MV), this chimera was rescued at high titers using reverse genetics in CD4+ target cells. Cytopathic effect consisted in the presence of large cell aggregates evolving to form syncytia, as observed during SIV infection. The morphology of the chimeric virus was identical to that of the parent MV particles. The presence of SIV gp160 as the only envelope protein on chimeric particles surface altered the cell tropism of the new virus from CD46+ to CD4+ cells. Used as an HIV candidate vaccine, this MV/SIVenv chimeric virus would mimic transient HIV-like infection, benefiting both from HIV-like tropism and the capacity of MV to replicate in dendritic cells, macrophages and lymphocytes.

  5. The effect of vitamin A on CD4+ and CD8+ cells irradiated by 60Co γ-ray

    International Nuclear Information System (INIS)

    The monocyte-depleted peripheral blood mononuclear cells were separated into CD4+ and CD8+ subpopulations by panning technique with McAb CD4 and CD8. The purity of CD4+ and CD8+ cells was 89.2% and 85.8% respectively, which was estimated by an indirect immunofluorescence technique. The radiosensitivities of CD4+ and CD8+ cells and the effect of DNA synthesis in both cells' subpopulations influenced by Vit A were assessed by 3H-TdR incorporation. The experimental result showed that after γ-radiation in different doses on CD4+ and CD8+ cells, the 3H-TdR incorporation was significantly decreased. The 3H-TdR incorporation rate in CD8+ cells irradiated with addition of 5 μg/ml Vit A increased significantly (p<0.05)

  6. 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...... lymphoid tissues of transplanted SCID mice proliferate in vitro in the presence of interleukin (IL)-2 + IL-7. CD3 ligation enhances this cytokine-supported proliferation in CD4+ T cells from the spleen and the mesenteric lymph node of transplanted SCID mice; CD3 ligation suppresses the cytokine...... fraction of colitis-inducing CD4+ T cells undergo activation-induced cell death in situ and can damage other cells through Fas-dependent cytotoxicity....

  7. Hsp70 enhances presentation of FMDV antigen to bovine CD4+ T cells in vitro

    OpenAIRE

    McLaughlin, Kerry; Seago, Julian; Robinson, Lucy; Kelly, Charles; Charleston, Bryan

    2010-01-01

    International audience Foot-and-mouth disease virus (FMDV) is the causative agent of a highly contagious acute vesicular disease affecting cloven-hoofed animals, including cattle, sheep and pigs. The current vaccine induces a rapid humoral response, but the duration of the protective antibody response is variable, possibly associated with a variable specific CD4+ T cell response. We investigated the use of heat shock protein 70 (Hsp70) as a molecular chaperone to target viral antigen to th...

  8. B Cells Regulate CD4+ T cell Responses to Papain Following BCR-Independent Papain Uptake

    OpenAIRE

    Dwyer, Daniel F.; Woodruff, Matthew C.; Carroll, Michael C.; Austen, K. Frank; Gurish, Michael F.

    2014-01-01

    Papain, a cysteine protease allergen with inherent adjuvant activity, induces potent IL4 expression by T cells in the popliteal lymph nodes (PLN) of mice following footpad immunization. Here we identify a novel, non-BCR mediated capacity for B cells to rapidly bind and internalize papain. B cells subsequently regulate the adaptive immune response by enhancing Inducible T cell Costimulator (ICOS) expression on CD4+ T cells and amplifying Th2 and T follicular helper induction. Antibody blockade...

  9. Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4+ T-Cell Clones

    OpenAIRE

    Norris, Philip J.; Sumaroka, Marina; Brander, Christian; Moffett, Howell F.; Boswell, Steven L.; Nguyen, Tam; Sykulev, Yuri; Walker, Bruce D; Rosenberg, Eric S.

    2001-01-01

    Mounting evidence suggests that human immunodeficiency virus type 1 (HIV-1) Gag-specific T helper cells contribute to effective antiviral control, but their functional characteristics and the precise epitopes targeted by this response remain to be defined. In this study, we generated CD4+ T-cell clones specific for Gag from HIV-1-infected persons with vigorous Gag-specific responses detectable in peripheral blood mononuclear cells. Multiple peptides containing T helper epitopes were identifie...

  10. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

    OpenAIRE

    Kuijpers, Taco W.; IJspeert, Hanna; Leeuwen, Ester; Jansen, Machiel H.; Mette D Hazenberg; Weijer, Kees; Van Lier, Rene A. W.; van der Burg, Mirjam

    2011-01-01

    textabstractA girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ r...

  11. Factors associated with poor CD4 and viral load outcomes in patients with HIV/AIDS.

    Science.gov (United States)

    Syed, Imran Ahmed; Sulaiman, Syed Azhar Syed; Hassali, Mohammad Azmi; Syed, Shahzad Hasan; Shan, Lau Hui; Lee, Christopher K C

    2016-05-01

    Suboptimal viral suppression and CD4 response to antiretroviral treatment (HAART) is known to cause poor outcomes with the increase cost of treatment. We aimed to assess factors associated with such control among HIV/AIDS patients in Malaysia. Four hundred and six HIV/AIDS patients, using Antiretroviral Therapy (ART) for at least the past three months, treated as outpatients at medication therapy adherence clinics (MTAC) were recruited. CD4 cell counts, viral load readings along with co-variants such as socio-demographic factors, adverse drug reactions, comorbidities, and medication record were obtained. Statistical Package for Social Sciences (SPSS(®) ) version 18 and STATA IC(®) version 12 were used for data analysis. CD4 counts were found highest among those within the age category 41-50 years (390.43 ± 272.28), female (402.64 ± 276.14), other ethnicities (400.20 ± 278.04), and participants with no formal education (414.87 ± 290.90). Patients experiencing adverse effects had a 2.28 (95%CI:1.25-4.18) fold greater risk of poor CD4 control, while patients with comorbidities had 2.46 (95%CI:1.02-5.91) fold greater risk of mild viral suppression. Adverse drug reactions, co-morbidities were found to be significantly associated with poor immunological and virological outcomes in HIV/AIDS patients. However, a comprehensive evaluation is needed to better understand other confounders J. Med. Virol. 88:790-797, 2016. © 2015 Wiley Periodicals, Inc. PMID:26399724

  12. Notch signalling inhibits CD4 expression during initiation and differentiation of human T cell lineage.

    Directory of Open Access Journals (Sweden)

    Stephen M Carlin

    Full Text Available The Delta/Notch signal transduction pathway is central to T cell differentiation from haemopoietic stem cells (HSCs. Although T cell development is well characterized using expression of cell surface markers, the detailed mechanisms driving differentiation have not been established. This issue becomes central with observations that adult HSCs exhibit poor differentiation towards the T cell lineage relative to neonatal or embryonic precursors. This study investigates the contribution of Notch signalling and stromal support cells to differentiation of adult and Cord Blood (CB human HSCs, using the Notch signalling OP9Delta co-culture system. Co-cultured cells were assayed at weekly intervals during development for phenotype markers using flow cytometry. Cells were also assayed for mRNA expression at critical developmental stages. Expression of the central thymocyte marker CD4 was initiated independently of Notch signalling, while cells grown with Notch signalling had reduced expression of CD4 mRNA and protein. Interruption of Notch signalling in partially differentiated cells increased CD4 mRNA and protein expression, and promoted differentiation to CD4(+ CD8(+ T cells. We identified a set of genes related to T cell development that were initiated by Notch signalling, and also a set of genes subsequently altered by Notch signal interruption. These results demonstrate that while Notch signalling is essential for establishment of the T cell lineage, at later stages of differentiation, its removal late in differentiation promotes more efficient DP cell generation. Notch signalling adds to signals provided by stromal cells to allow HSCs to differentiate to T cells via initiation of transcription factors such as HES1, GATA3 and TCF7. We also identify gene expression profile differences that may account for low generation of T cells from adult HSCs.

  13. CD4+ T cell immunity to the Burkholderia pseudomallei ABC transporter LolC in melioidosis

    OpenAIRE

    Chu, Karen K.; Tippayawat, Patcharaporn; Walker, Nicola J.; Harding, Sarah V.; Atkins, Helen S.; Maillere, Bernard; Bancroft, Gregory J; Lertmemongkolchai, Ganjana; Altmann, Daniel M

    2010-01-01

    Burkholderia pseudomallei (Bp) causes melioidosis, a disease with a wide range of possible outcomes, from seroconversion and dormancy to sepsis and death. This spectrum of host-pathogen interactions poses challenging questions about heterogeneity in immunity to Bp. Models show protection to be dependent on CD4+ cells and IFNγ, but little is known about specific target antigens. Having previously implicated the ABC transporter, LolC, in protective immunity, we here use epitope prediction, HLA ...

  14. CD4+ T cell responses to self- and mutated p53 determinants during tumorigenesis in mice.

    Science.gov (United States)

    Fedoseyeva, E V; Boisgérault, F; Anosova, N G; Wollish, W S; Arlotta, P; Jensen, P E; Ono, S J; Benichou, G

    2000-06-01

    We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225-239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225-239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225-239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225-239 self-reactive T cells. PMID:10820239

  15. Subsets of human CD4+ regulatory T cells express the peripheral homing receptor CXCR3

    OpenAIRE

    Hoerning, André; Koss, Kerith; Datta, Dipak; Boneschansker, Leonard; Jones, Caroline N.; Wong, Ian Y.; Irimia, Daniel; Calzadilla, Katiana; Benitez, Fanny; Hoyer, Peter F.; Harmon, William E.; Briscoe, David M.

    2011-01-01

    Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that ~30–40% of human CD25hi FOXP3+ CD4+ Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-γ production were significantly higher using CXCR3-depleted versus undeplete...

  16. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17

    OpenAIRE

    Park, Heon; Li, Zhaoxia; Yang, Xuexian O.; Chang, Seon Hee; Nurieva, Roza; Wang, Yi-hong; Wang, Ying; Hood, Leroy; Zhu, Zhou; Tian, Qiang; Dong, Chen

    2005-01-01

    Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interfero...

  17. Innate memory CD4+ T cells suppress autoimmune graft-versus-host disease

    OpenAIRE

    Weishan Huang; Jianfang Hu; Laufer, Terri M.

    2013-01-01

    Chronic graft-versus-host disease (cGVHD) is the major complication post hematopoietic cell transplantation. Major histocompatibility complex class II (MHCII) mediated CD4+ T cell differentiation and function plays a critical role in cGVHD, and the lack of hematopoietic MHCII (H-MHCII) causes cGVHD in syngeneic irradiated murine recipients. We have studied this process using murine bone marrow transplant of MHCII deficient or sufficient donors. We find that irradiated WT recipients that recei...

  18. Electroacupuncture Attenuates Ovalbumin-Induced Allergic Asthma via Modulating CD4+CD25+ Regulatory T Cells

    OpenAIRE

    Youngjoo Kwon; Sung-Hwa Sohn; Gihyun Lee; Youngeun Kim; Hyejung Lee; Minkyu Shin; Hyunsu Bae

    2012-01-01

    A mouse pulmonary hypersensitivity experimental model that mimics human asthma was developed, and electroacupuncture (EA) treatment was shown to reduce allergic inflammatory processes. In addition, we also assessed whether the beneficial effects of EA on allergic asthma could be correlated with CD4+CD25+Foxp3+ regulatory T cells (Treg). Cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in ...

  19. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells

    OpenAIRE

    Deborah H Strickland; Stumbles, Philip A.; Zosky, Graeme R.; Subrata, Lily S.; Thomas, Jenny A.; Turner, Debra J.; Sly, Peter D.; Holt, Patrick G.

    2006-01-01

    An important feature of atopic asthma is the T cell–driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+...

  20. Plastizität von CD4-positiven T-Lymphozyten im Kontext einer Helmintheninfektion

    OpenAIRE

    Panzer, Marc

    2013-01-01

    Das Immunsystem von Säugern wird durch Pathogene, Allergene oder ebenso durch körpereigene Autoantigene stimuliert. Diese Stimulation resultiert in einer Differenzierung von CD4-positiven T-Zellen, die je nach eingeleiteter Immunantwort ihre entzündungsfördernden oder hemmenden Effektorfunktionen ausüben können. Basierend auf den funktionellen Eigenschaften und einem spezifischen Transkriptionsfaktorprofil sowie Zytokinsekretionsprofil lassen sich diese reaktiven Effektorzellen in Th1-, Th2-,...

  1. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria.

    Science.gov (United States)

    Hepworth, Matthew R; Monticelli, Laurel A; Fung, Thomas C; Ziegler, Carly G K; Grunberg, Stephanie; Sinha, Rohini; Mantegazza, Adriana R; Ma, Hak-Ling; Crawford, Alison; Angelosanto, Jill M; Wherry, E John; Koni, Pandelakis A; Bushman, Frederic D; Elson, Charles O; Eberl, Gérard; Artis, David; Sonnenberg, Gregory F

    2013-06-01

    Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal

  2. Proximal signaling control of human effector CD4 T cell function

    OpenAIRE

    Okoye, Francesca I.; Krishnan, Sandeep; Chandok, Meena R.; Tsokos, George C.; Farber, Donna L.

    2007-01-01

    The functional coupling of T cell receptor (TCR)-mediated signaling events in primary human T cells remains undefined. We demonstrate here that alterations in the expression of proximal TCR-coupled signaling subunits are associated with distinct effector capacities in differentiated human CD4 T cells. Analysis of proximal signaling profiles using biochemical and single cell approaches reveals decreased CD3ζ and ZAP-70 expression correlating with functional anergy, with increased CD3ζ/ZAP-70 e...

  3. Regulatory T cells diminish transmission of HIV from Dendritic cells to conventional CD4+ T cells

    OpenAIRE

    Maria Eugenia Moreno-Fernandez; Joedicke, Jara J; Claire Anne Chougnet

    2014-01-01

    Formation of immunological synapses between dendritic cells (DC) and conventional CD4+ T cells (Tcon) is critical for productive immune responses. However, when DCs are HIV-infected such synapses are critical to establish HIV infection. As regulatory T cells (Treg) control DC-Tcon interactions, we inquired whether Treg might interfere with DC to Tcon HIV transmission. We developed a model, using monocyte-derived DC infected with R5-HIV, and cultured with Tcon in the presence or absence of a...

  4. TCR repertoire and Foxp3 expression define functionally distinct subsets of CD4+ Treg cells1

    OpenAIRE

    Kuczma, Michal; Pawlikowska, Iwona; Kopij, Magdalena; Podolsky, Robert; Rempala, Grzegorz A.; Kraj, Piotr

    2009-01-01

    Despite extensive research efforts to characterize peripheral regulatory T cells (Treg) expressing transcription factor Foxp3, their subset complexity, phenotypic characteristics, TCR repertoire and antigen specificities remain ambiguous. Here, we identify and define two subsets of peripheral Treg cells differing in Foxp3 expression level and TCR repertoires. Treg cells expressing a high level of Foxp3 and TCRs not utilized by naive CD4+ T cells present a stable suppressor phenotype and domin...

  5. Nutritional status and CD4 cell counts in patients with HIV/AIDS receiving antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Ana Celia Oliveira dos Santos

    2013-12-01

    Full Text Available Introduction Even with current highly active antiretroviral therapy, individuals with AIDS continue to exhibit important nutritional deficits and reduced levels of albumin and hemoglobin, which may be directly related to their cluster of differentiation 4 (CD4 cell counts. The aim of this study was to characterize the nutritional status of individuals with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS and relate the findings to the albumin level, hemoglobin level and CD4 cell count. Methods Patients over 20 years of age with AIDS who were hospitalized in a university hospital and were receiving antiretroviral therapy were studied with regard to clinical, anthropometric, biochemical and sociodemographic characteristics. Body mass index, percentage of weight loss, arm circumference, triceps skinfold and arm muscle circumference were analyzed. Data on albumin, hemoglobin, hematocrit and CD4 cell count were obtained from patient charts. Statistical analysis was performed using Fisher's exact test, Student's t-test for independent variables and the Mann-Whitney U-test. The level of significance was set to 0.05 (α = 5%. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS 17.0 software for Windows. Results Of the 50 patients evaluated, 70% were male. The prevalence of malnutrition was higher when the definition was based on arm circumference and triceps skinfold measurement. The concentrations of all biochemical variables were significantly lower among patients with a body mass index of less than 18.5kg/m2. The CD4 cell count, albumin, hemoglobin and hematocrit anthropometric measures were directly related to each other. Conclusions These findings underscore the importance of nutritional follow-up for underweight patients with AIDS, as nutritional status proved to be related to important biochemical alterations.

  6. Long-term control of CMV retinitis in a patient with idiopathic CD4+ T lymphocytopenia.

    Science.gov (United States)

    Yashiro, Shigeko; Fujino, Yujiro; Tachikawa, Natsuo; Inamochi, Kazuya; Oka, Shinichi

    2013-04-01

    Cytomegalovirus (CMV) retinitis with idiopathic CD4(+) T lymphocytopenia (ICL) is rare and difficult to control. We report a first case for long-term control of CMV retinitis with ICL using interleukin-2 (IL-2) therapy and succeeded in discontinuation of anti-CMV therapy. A 49-year-old Japanese woman was diagnosed with ICL based on low CD4(+) count (72/μl), negative for HIV-1 and -2 antibodies, and absence of any defined immunodeficiency diseases or immunosuppressive therapy. PCR test of the aqueous humor in the right eye was suggestive of CMV retinitis. She was treated with systemic ganciclovir, but after several relapses of CMV retinitis, rhegmatogenous retinal detachment appeared in the right eye and she became blind in that eye. Three years later, she developed CMV retinitis in the left eye. Although she received systemic and focal anti-CMV treatments, the retinitis showed no improvement. Finally, retinal detachment occurred, and she underwent vitrectomy. IL-2 was injected to increase CD4(+) counts. Because of hyperpyrexia, blepharedema, central scotoma, and color anomaly, we changed to low-dose IL-2 therapy with no side effects. Finally, we succeeded in increasing the CD4(+) count to more than 200/μl after discontinuation of low-dose IL-2 therapy. CMV retinitis never recurred after discontinuation of anti-CMV therapy, with good visual acuity of 20/20 in the left eye. She developed blindness of the first affected right eye, whereas the visual acuity of the left eye remains excellent more than 12 years after the onset of CMV retinitis through the combined use of anti-CMV therapy, IL-2 therapy, and vitrectomy. PMID:22935818

  7. Friend of GATA-1 Represses GATA-3–dependent Activity in CD4+ T Cells

    OpenAIRE

    Zhou, Meixia; Ouyang, Wenjun; Gong, Qian; Katz, Samuel G.; White, J. Michael; Orkin, Stuart H.; Murphy, Kenneth M.

    2001-01-01

    The development of naive CD4+ T cells into a T helper (Th) 2 subset capable of producing interleukin (IL)-4, IL-5, and IL-13 involves a signal transducer and activator of transcription (Stat)6-dependent induction of GATA-3 expression, followed by Stat6-independent GATA-3 autoactivation. The friend of GATA (FOG)-1 protein regulates GATA transcription factor activity in several stages of hematopoietic development including erythrocyte and megakaryocyte differentiation, but whether FOG-1 regulat...

  8. Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4+ Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication

    Science.gov (United States)

    Schmitt, Nathalie; Chêne, Laurent; Boutolleau, David; Nugeyre, Marie-Thérèse; Guillemard, Eric; Versmisse, Pierre; Jacquemot, Catherine; Barré-Sinoussi, Françoise; Israël, Nicole

    2003-01-01

    The emergence of X4 human immunodeficiency virus type 1 (HIV-1) variants in infected individuals is associated with poor prognosis. One of the possible causes of this emergence might be the selection of X4 variants in some specific tissue compartment. We demonstrate that the thymic microenvironment favors the replication of X4 variants by positively modulating the expression and signaling of CXCR4 in mature CD4+ CD8− CD3+ thymocytes. Here, we show that the interaction of thymic epithelial cells (TEC) with these thymocytes in culture induces an upregulation of CXCR4 expression. The cytokine secreted by TEC, interleukin-7 (IL-7), increases cell surface expression of CXCR4 and efficiently overcomes the downregulation induced by SDF-1α, also produced by TEC. IL-7 also potentiates CXCR4 signaling, leading to actin polymerization, a process necessary for virus entry. In contrast, in intermediate CD4+ CD8− CD3− thymocytes, the other subpopulation known to allow virus replication, TEC or IL-7 has little or no effect on CXCR4 expression and signaling. CCR5 is expressed at similarly low levels in the two thymocyte subpopulations, and neither its expression nor its signaling was modified by the cytokines tested. This positive regulation of CXCR4 by IL-7 in mature CD4+ thymocytes correlates with their high capacity to favor X4 virus replication compared with intermediate thymocytes or peripheral blood mononuclear cells. Indeed, we observed an enrichment of X4 viruses after replication in thymocytes initially infected with a mixture of X4 (NL4-3) and R5 (NLAD8) HIV strains and after the emergence of X4 variants from an R5 primary isolate during culture in mature thymocytes. PMID:12719571

  9. Risks of Cervical Cancer Screening

    Science.gov (United States)

    ... Treatment Cervical Cancer Prevention Cervical Cancer Screening Research Cervical Cancer Screening (PDQ®)–Patient Version What is screening? Screening ... These are called diagnostic tests . General Information About Cervical Cancer Key Points Cervical cancer is a disease in ...

  10. Oct1 and OCA-B are selectively required for CD4 memory T cell function.

    Science.gov (United States)

    Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean

    2015-11-16

    Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. PMID:26481684

  11. Public T cell receptors confer high-avidity CD4 responses to HIV controllers.

    Science.gov (United States)

    Benati, Daniela; Galperin, Moran; Lambotte, Olivier; Gras, Stéphanie; Lim, Annick; Mukhopadhyay, Madhura; Nouël, Alexandre; Campbell, Kristy-Anne; Lemercier, Brigitte; Claireaux, Mathieu; Hendou, Samia; Lechat, Pierre; de Truchis, Pierre; Boufassa, Faroudy; Rossjohn, Jamie; Delfraissy, Jean-François; Arenzana-Seisdedos, Fernando; Chakrabarti, Lisa A

    2016-06-01

    The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure. PMID:27111229

  12. Characteristics of TCRαβ+CD4-CD8- thymocytes in fetal thymic organ culture

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    TCRαβ+CD4-CD8- (TCR+ DN) thymocytes at different developmental periods, i.e. after either 9 or 18 days of culture in the fetal thymic organ culture (FTOC) system, were characterized in the properties of phenotype, proliferation, differentiation and apoptosis. The results showed that anti-CD3 mAb significantly promoted proliferation of TCRαβ+ DN cells generated after 18 days of culture in FTOC, whereas the cells generated after 9 days of culture responded to anti-CD3 mAb by proliferation weakly. IL-7 efficiently induced TCRαβ+ DN cells at day 9 of FTOC to differentiate into TCRαβ+CD4+/CD8+ SP cells without detectable transitional stage of TCRαβ+CD4+CD8+ (DP) cells. In contrast, fewer TCRαβ+ DN cells generated after 18 days of FTOC were induced to differentiate into SP cells. The thymic stromal cell line MTEC5 cells synergized with IL-7 to promote the differentiation of TCRαβ+ DN cells. In addition, TCRαβ+ DN cells were shown to be less susceptible to apoptosis compared with the other major thymocyte subsets. Taken together, these data have provided insight into the characteristics of TCRαβ+ DN thymocytes.

  13. Novel function of perforin in negatively regulating CD4+T cell activation by affecting calcium signaling

    Institute of Scientific and Technical Information of China (English)

    Enguang Bi; Kairui Mao; Jia Zou; Yuhan Zheng; Bing Sun; Chunjian Huang; Yu Hu; Xiaodong Wu; Weiwen Deng; Guomei Lin; Zhiduo Liu; Lin Tian; Shuhui Sun

    2009-01-01

    Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic Tlymphocytes (CTLs) and natural killer cells. However, whether it also plays a role in conventional CD4+ T cell func-tion remains unclear. Here we report that in perforin-deficient (PKO) mice, CD4+ T cells are hyperproliferative in response to T cell receptor (TCR) stimulation. This feature of hyperproliferation is accompanied by the enhancement both in cell division and in IL-2 secretion. It seems that the perforin deficiency does not influence T cell development in thymus spleen and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell prolifera-tion and antibody production. Furthermore, PKO mice are more susceptible to experimental autoimmune uveitis. To address the molecular mechanism, we found that after TCR stimulation, CD44 T cells from PKO mice display an increased intracellular calcium flux and subsequently enhance activation of transcription factor NFATI. Our results indicate that perforin plays a negative role in regulating CD4+ T cell activation and immune response by affecting TCR-dependent Ca2+ signaling.

  14. Clinical profile of neurological complications in HIV-reactive patients and their relation with CD4

    Directory of Open Access Journals (Sweden)

    Dhadke S.V

    2014-07-01

    Full Text Available Background: Neurologic abnormalities have been noted in one-third of patients with AIDS, but at autopsy the nervous system is affected in all of them. Aim: To study the clinical profile of neurological complications in HIV reactive patients, study and correlate the neurological complications with CD4 count and study and correlate the radiological findings (on CT brain plain and contrast of neurological complications in HIV reactive patients, with CD4count. Methods: A randomized case study was conducted at Dr. V. M. Government Medical College, Solapur, Maharashtra, India, over a period of 2 years. 50 HIV-infected adult and adolescent patients presenting with neurological manifestations were studied. The diagnosis of HIV was confirmed by 3 HIV ELISA positive reports in symptomatic patients. Results: In the present study, 46% of the patients were in the age group of 31-40 years. Males are affected more frequently than females, with a male to female sex ratio of 2.125: 1. Meningitis, intracranial space occupying lesions, and stroke syndromes are the commonest neurological disorders observed in HIV-infected patients. Tuberculosis is the commonest opportunistic infection in retroviral positive patients. Ischemic strokes are a common complication in HIV-infected individuals. Tuberculomas are the most common cause of intracranial space occupying lesions. Conclusion: Central nervous system infections, intracranial mass lesions, stroke, and HIV-associated dementia are more common in patients with a CD4+ count less than 200.

  15. Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy

    Directory of Open Access Journals (Sweden)

    Mark J Dobrzanski

    2013-03-01

    Full Text Available The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for "plasticity" and memory cell generation within the hostile tumor environment and their potentials in cancer treatment and adoptive immunotherapies.

  16. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes.

    Science.gov (United States)

    Every, Alison L; Kramer, David R; Mannering, Stuart I; Lew, Andrew M; Harrison, Leonard C

    2006-04-15

    Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T(reg)) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ T(reg) that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+ CD25+ T(reg), CD4+ T(reg) induced by proinsulin DNA were both CD25+ and CD25- and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T(reg) and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T(reg), but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity. PMID:16585551

  17. Electroacupuncture Attenuates Ovalbumin-Induced Allergic Asthma via Modulating CD4+CD25+ Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Youngjoo Kwon

    2012-01-01

    Full Text Available A mouse pulmonary hypersensitivity experimental model that mimics human asthma was developed, and electroacupuncture (EA treatment was shown to reduce allergic inflammatory processes. In addition, we also assessed whether the beneficial effects of EA on allergic asthma could be correlated with CD4+CD25+Foxp3+ regulatory T cells (Treg. Cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in the EA-treated groups when compared to the OVA and anti-CD25 Ab-injected (Treg depletion groups. Furthermore, total BAL cells were reduced in the EA groups when compared to other groups. Interestingly, the population of CD4+CD25+Foxp3+Tregs in pneumonocytes increased in EA-treated group when compared to OVA and Treg depletion groups. These results imply that EA stimulation at ST 36 may affect CD4+CD25+Foxp3+ Treg in an OVA-induced experimental model and may enhance Treg function by suppressing other T cells and limiting the immune response.

  18. Evaluation of the Effect of IL-22 on Human Cord Blood CD4+ T Cells

    Directory of Open Access Journals (Sweden)

    Javad Arasteh

    2010-06-01

    Full Text Available IL-22 is a member of IL-10 cytokine family which is believed to play an important role in inflammatory responses. IL-22 has similarities with IL-10 including conserved sequences with IL-10. IL-22 receptor is also comprised of two chains known as L-22R1 and L-10R2; supporting the speculation that the two cytokines may have similar effects. The aim of this study was to shed some light on the biological activity of IL-22 upon the cord blood CD4+CD25- T cells. In this research, cord blood T CD4+CD25- cells were cultured in presence of anti CD2/CD3/CD28 coated beads, IL-2 and IL-22 for two weeks at 37 oC and 5% CO2. Flow cytometry analysis showed that IL-22 has no effect upon CD25 and Foxp3 expression. Also, the results indicated that IL-22 is not involved in CD4+ T cell proliferation. Moreover, the results of suppression assay did not show any suppression effect on the cultured T cells. Thus, it seems that umbilical cord blood T cells probably do not express IL-22R1 on their surface.

  19. Patterns of CD4+ T-lymphocytes and liver enzymes in adult HIV seropositive cases

    Directory of Open Access Journals (Sweden)

    Saheed O. Usman

    2015-12-01

    Full Text Available Objectives: HIV/AIDS is a rapidly growing epidemic in sub-Saharan Africa, in particular Nigeria. HIV is a retrovirus that primarily infects components of the human immune system such as CD4+ T-cells, macrophages and dendritic cells. This study is therefore designed to evaluate the CD4+ T-cell count and liver enzymes of adult HIV seropositive subjects receiving Highly Active Antiretroviral Therapy (HAART and those yet to be started on HAART as well as HIV seronegative control subjects. Methods: Serum levels of CD4+ counts of subjects were determined using flow cytometry while their serum alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP were determined using enzymatic spectrophotometric method. Results: Serum ALT was found to be significantly increased in the HAART group as compared with those of the two other groups. In addition, serum ALP was significantly increased in the HAART group as compared with the control subjects, while serum AST was higher in the HAART group as compared with the HAART naive group. Conclusion: HAART is associated with hepatotoxicity, thus, it is recommended that liver enzymes should be measured before and periodically after antiretroviral therapy is initiated and/or when HAART regimen is switched, as this will serve a good index for disease monitoring and/or progression. [J Exp Integr Med 2015; 5(4.000: 178-182

  20. Transcription regulates HIF-1α expression in CD4(+) T cells.

    Science.gov (United States)

    Bollinger, Thomas; Bollinger, Annalena; Gies, Sydney; Feldhoff, Lea; Solbach, Werner; Rupp, Jan

    2016-01-01

    The transcription factor hypoxia inducible factor-1α (HIF-1α) mediates the metabolic adaptation of cells to hypoxia and T-helper cell fate. However, HIF-1α regulation in CD4(+) T cells (T cells) remains elusive. Here we observed that depletion of oxygen (O2⩽2%) alone was not sufficient to induce HIF-1α expression in T cells. However, when hypoxic T cells were stimulated, HIF-1α was expressed and this was dependent on nuclear factor-κB- and nuclear factor of activated T cell (NFAT)-mediated transcriptional upregulation of Hif-1α mRNA. HIF-1α upregulation could be blocked by drugs inhibiting NF-κB, NFAT or mammalian target of rapamycin precluding CD4(+) T-cell stimulation or translation in T cells, as well as by blocking transcription. CD3, CD28, phorbol-12-myristat-13-acetat (PMA) or ionomycin-stimulated T cells did not express HIF-1α under normoxic conditions. In conclusion, regulation of HIF-1α expression in CD4(+) T cells in hypoxia gravely relies on its transcriptional upregulation and subsequent enhanced protein stabilization. PMID:26150319

  1. CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Birjandi, Shirin Z; Palchevskiy, Vyacheslav; Xue, Ying Ying; Nunez, Stefanie; Kern, Rita; Weigt, S Sam; Lynch, Joseph P; Chatila, Talal A; Belperio, John A

    2016-08-01

    Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-β) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis. PMID:27317904

  2. Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla.

    Directory of Open Access Journals (Sweden)

    Magali Irla

    Full Text Available The thymic medulla is dedicated for purging the T-cell receptor (TCR repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4⁺ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4⁺ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4⁺ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.

  3. Cervical spine CT scan

    Science.gov (United States)

    ... cervical spine; Computed tomography scan of cervical spine; CT scan of cervical spine; Neck CT scan ... Risks of CT scans include: Being exposed to radiation Allergic reaction to contrast dye CT scans expose you to more radiation than ...

  4. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation.

    Science.gov (United States)

    Makita, Shin; Kanai, Takanori; Nemoto, Yasuhiro; Totsuka, Teruji; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Yamamoto, Masafumi; Kiyono, Hiroshi; Watanabe, Mamoru

    2007-04-15

    It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (T(REG)) cells play an important role in the normal intestinal homeostasis, but also that its dysregulation of immune response leads to the development of inflammatory bowel disease. In this study, we demonstrate that murine CD4(+)CD25(+) T cells residing in the intestinal lamina propria (LP) constitutively express CTLA-4, glucocorticoid-induced TNFR, and Foxp3 and suppress proliferation of responder CD4(+) T cells in vitro. Furthermore, cotransfer of intestinal LP CD4(+)CD25(+) T cells prevents the development of chronic colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells into SCID mice. When lymphotoxin (LT)alpha-deficient intercrossed Rag2 double knockout mice (LTalpha(-/-) x Rag2(-/-)), which lack mesenteric lymph nodes and Peyer's patches, are transferred with CD4(+)CD45RB(high) T cells, they develop severe wasting disease and chronic colitis despite the delayed kinetics as compared with the control LTalpha(+/+) x Rag2(-/-) mice transferred with CD4(+)CD45RB(high) T cells. Of note, when a mixture of splenic CD4(+)CD25(+) T(REG) cells and CD4(+)CD45RB(high) T cells are transferred into LTalpha(-/-) x Rag2(-/-) recipients, CD4(+)CD25(+) T(REG) cells migrate into the colon and prevent the development of colitis in LTalpha(-/-) x Rag2(-/-) recipients as well as in the control LTalpha(+/+) x Rag2(-/-) recipients. These results suggest that the intestinal LP harboring CD4(+)CD25(+) T(REG) cells contributes to the intestinal immune suppression. PMID:17404275

  5. The early activation marker CD69 regulates the expression of chemokines and CD4 T cell accumulation in intestine.

    Directory of Open Access Journals (Sweden)

    Katarina Radulovic

    Full Text Available Migration of naïve and activated lymphocytes is regulated by the expression of various molecules such as chemokine receptors and ligands. CD69, the early activation marker of C-type lectin domain family, is also shown to regulate the lymphocyte migration by affecting their egress from the thymus and secondary lymphoid organs. Here, we aimed to investigate the role of CD69 in accumulation of CD4 T cells in intestine using murine models of inflammatory bowel disease. We found that genetic deletion of CD69 in mice increases the expression of the chemokines CCL-1, CXCL-10 and CCL-19 in CD4(+ T cells and/or CD4(- cells. Efficient in vitro migration of CD69-deficient CD4 T cells toward the chemokine stimuli was the result of increased expression and/or affinity of chemokine receptors. In vivo CD69(-/- CD4 T cells accumulate in the intestine in higher numbers than B6 CD4 T cells as observed in competitive homing assay, dextran sodium sulphate (DSS-induced colitis and antigen-specific transfer colitis. In DSS colitis CD69(-/- CD4 T cell accumulation in colonic lamina propria (cLP was associated with increased expression of CCL-1, CXCL-10 and CCL-19 genes. Furthermore, treatment of DSS-administrated CD69(-/- mice with the mixture of CCL-1, CXCL-10 and CCL-19 neutralizing Abs significantly decreased the histopathological signs of colitis. Transfer of OT-II×CD69(-/- CD45RB(high CD4 T cells into RAG(-/- hosts induced CD4 T cell accumulation in cLP. This study showed CD69 as negative regulator of inflammatory responses in intestine as it decreases the expression of chemotactic receptors and ligands and reduces the accumulation of CD4 T cells in cLP during colitis.

  6. Autocrine production of beta-chemokines protects CMV-Specific CD4 T cells from HIV infection.

    Directory of Open Access Journals (Sweden)

    Joseph P Casazza

    2009-10-01

    Full Text Available Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1alpha and MIP-1beta mRNA, resulting in a rapid increase in production of MIP-1alpha and MIP-1beta after cognate antigen stimulation. Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of beta-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1beta contained 10 times less Gag DNA than did those which failed to produce MIP-1beta. These data suggest that CD4+ T cells which produce MIP-1alpha and MIP-1beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.

  7. Role of regulatory CD4+CD25+ Foxp3 T cells in bronchial asthma in Egyptian children.

    Science.gov (United States)

    Bakr, Salwa I; Mahran, Manal Z; Soliman, Dina A

    2013-01-01

    CD4+CD25+high Foxp3 regulatory T (Treg) cells are known to play a key role in balancing immune response to maintain peripheral tolerance against harmless antigens or allergens. Defective immunological suppression by CD4+CD25+high Foxp3 Treg cells can be a cause of the inflammation that leads to an allergic condition such as asthma. The aims of the study are to (1) determine CD4+CD25+high Foxp3 Treg cells frequency in the peripheral blood of children with and without asthma; and (2) investigate the association between CD4+CD25+high Foxp3 Treg cells frequency with disease severity and corticosteroid therapy. Sixty asthmatic children with varying disease severity (20 mild, 20 moderate and 20 severe) were enrolled in the study. Severe asthmatic children were further subdivided into two groups, one on corticosteroid therapy and the other was not on corticosteroid. Twenty age and sex matched healthy children were enrolled as controls. Number of circulating CD4+CD25+high Foxp3 Tregs were measured using flow cytometry. Our finding demonstrates that children with asthma had a significant decrease of CD4+CD25high Foxp3 Treg cells and Tregs/T effectors ratio in peripheral blood compared to children without asthma. Patients with moderate asthma demonstrated lower frequency of CD4+CD25+high Foxp3 Treg cells compared to mild and severe asthmatic patients. Those on corticosteroid therapy revealed significant increase in CD4+CD25+high Foxp3 Treg cells and decrease in T effectors. It is concluded that asthmatic children have decreased number of CD4+CD25+high Foxp3 Treg cells leading to increase in effectors cells which mediate inflammation in the airways. Corticosteroid therapy plays a role in elevating number of CD4+CD25+high Foxp3 Treg cells and maintaining its suppressor function. PMID:24617045

  8. Evaluation of portable point-of-care CD4 counter with high sensitivity for detecting patients eligible for antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Yukari C Manabe

    Full Text Available BACKGROUND: Accurate, inexpensive point-of-care CD4+ T cell testing technologies are needed that can deliver CD4+ T cell results at lower level health centers or community outreach voluntary counseling and testing. We sought to evaluate a point-of-care CD4+ T cell counter, the Pima CD4 Test System, a portable, battery-operated bench-top instrument that is designed to use finger stick blood samples suitable for field use in conjunction with rapid HIV testing. METHODS: Duplicate measurements were performed on both capillary and venous samples using Pima CD4 analyzers, compared to the BD FACSCalibur (reference method. The mean bias was estimated by paired Student's t-test. Bland Altman plots were used to assess agreement. RESULTS: 206 participants were enrolled with a median CD4 count of 396 (range; 18-1500. The finger stick PIMA had a mean bias of -66.3 cells/µL (95%CI -83.4-49.2, P500 cells/µL with a mean bias of -120.6 (95%CI -162.8, -78.4, P<0.001. The sensitivity (95%CI of the Pima CD4 analyzer was 96.3% (79.1-99.8% for a <250 cells/ul cut-off with a negative predictive value of 99.2% (95.1-99.9%. CONCLUSIONS: The Pima CD4 finger stick test is an easy-to-use, portable, relatively fast device to test CD4+ T cell counts in the field. Issues of negatively-biased CD4 cell counts especially at higher absolute numbers will limit its utility for longitudinal immunologic response to ART. The high sensitivity and negative predictive value of the test makes it an attractive option for field use to identify patients eligible for ART, thus potentially reducing delays in linkage to care and ART initiation.

  9. Laminoplasty for Cervical Myelopathy

    OpenAIRE

    Ito, Manabu; Nagahama, Ken

    2012-01-01

    This article reviews cervical laminoplasty. The origin of cervical laminoplasty dates back to cervical laminectomy performed in Japan ~50 years ago. To overcome poor surgical outcomes of cervical laminectomy, many Japanese orthopedic spine surgeons devoted their lives to developing better posterior decompression procedures for the cervical spine. Thanks to the development of a high-speed surgical burr, posterior decompression procedures for the cervical spine showed vast improvement from the ...

  10. The Detection and Significance of CD4+CD25+CD127lo/-Tregs in Peripheral Blood CD4+T Cells of Healthy and Asthma Patients during Exacerbation and Remission%急性发作期和缓解期哮喘患者外周血CD4+CD25+CD127lo/-Treg的检测和意义

    Institute of Scientific and Technical Information of China (English)

    上官文姬; 沈惠风; 王利民; 叶人诵

    2011-01-01

    目的:通过检测健康人、急性发作期和缓解期哮喘患者外周血CD4+CD25+CD127lo/-Treg细胞的表达水平,探讨该细胞表达水平的变化与哮喘患者病情严重程度的关系.方法:采集急性发作期、缓解期哮喘患者及健康人外周抗凝血,用流式细胞术检测其外周血中CD4+CD25+CD127lo/-Treg细胞占CD4+T细胞的比例.结果:哮喘急性发作组和缓解组患者外周血中CD4+CD25+CD127lo/-Treg细胞占CD4+T细胞的百分比低于健康对照组(P<0.05);哮喘急性发作期组CD4+CD25+CD127lo/-Treg细胞占CD4+T细胞的百分比低于哮喘缓解组(P<0.05).结论:CD4+CD25+ CD127lo/-Treg细胞数量减少可能参与了哮喘的发病过程.%Objective:To investigate the relationship between the expression levels of CD4 + CD25 + CD127lo/-Tregs in peripheral blood of asthma patients during exacerbation or remission. Methods: A total of 2 ml peripheral blood were collected in healthy or asthma patients during exacerbation and remission. The percentage of CD4+ CD25 + CDl27lo/-Tregs in CD4+ T cells by flow cytometry were detected. Results: A significant decrease of the percentage of CD4+ CD25+ CD127lo/- Tregs in CD4+ T cells was observed in exacerbation and remission groups compared with control group (P<0.05). This was also detected in exacerbation group compared with remission group (P<0.05). Conclusions: The CD4+ CD25+ CD127lo/-Tregs play a key role in the pathogenesis of asthma and its decrease,which may lead to immune dysfunction, may be involved in the mechanisms of asthma.

  11. HIV感染者CD4+T淋巴细胞计数与牙龈出血指数的关系%The correlation of CD4 + T lymphocyte count and gingivai bleeding index in HIV-positive patients

    Institute of Scientific and Technical Information of China (English)

    王璇; 刘静明; 贾洪诚; 付茜; 李晓光; 柳月红; 杨昆

    2011-01-01

    Objective To investigate the correlation of CD4 + T lymphocyte count and gingival bleeding index in HIV-positive patients. Methods Seventy-nine HIV-positive patients were selected according to inclusioncriteria. Periodontal examination included plaque index ( PLI) and gingival bleeding index (BI), and CD4 + T lymphocytes were counted. Results The BIs were 1-2 in 54. 05% of patients with CD4 SOOcells /mm3 respectively. No correlation was found between CD4 cell counts and BI when all patients were evaluated. Positive correlations were observed between CD4 cell counts and BI for the subpopulations with CD4 500cells /mm3 showed no association between CD4 cell count and BI.%目的 初步探讨HⅣ阳性患者CD4 +T淋巴细胞计数与牙龈出血指数的关系.方法 随机选择符合纳入标准的受试者79名.检查受试者菌斑指数、出血指数和血液CD4 +T淋巴细胞计数.结果 CD4 +T淋巴细胞计数< 200个/mm3者中,54.05%出血指数为1~2;200~500个/mm3者中,57.58%出血指数为2~4; >500个/mm3者中,55.56%出血指数为0~1.总体来看,CD4 +T淋巴细胞计数与HIV感染者牙龈出血指数无相关关系(P>0.05);CD4 +T淋巴细胞计数分层后,并控制菌斑指数进行偏相关分析,CD4 +T淋巴细胞计数<200个/mm3和200 ~ 500个/mm3者偏相关系数分别0.612(P=0.000)、0.353(P=0.048),CD4 +T淋巴细胞计数和出血指数有相关性,2组出血指数分别是1.410±0.791和1.904±1.201,差异有显著性(P<0.05).结论 CD4 +T淋巴细胞计数<500个/mm3的HIV感染者的牙龈出血指数和CD4 +T淋巴细胞计数有相关性,且中度免疫抑制者牙龈出血指数高于重度免疫抑制者.而CD4 +T淋巴细胞计数>500个/mm3的HIV感染者的牙龈出血指数和CD4+T淋巴细胞计数没有相关性.

  12. Percentages of CD4+CD161+ and CD4−CD8−CD161+ T Cells in the Synovial Fluid Are Correlated with Disease Activity in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Jinlin Miao

    2015-01-01

    Full Text Available Objective. CD161 has been identified as a marker of human IL-17-producing T cells that are implicated in the pathogenesis of rheumatoid arthritis (RA. This study aimed to investigate the potential link between the percentage of CD161+ T cells and disease activity in RA patients. Methods. Peripheral blood (PB from 54 RA patients and 21 healthy controls was evaluated. Paired synovial fluid (SF (n = 17 was analyzed. CD161 expression levels on CD4+, CD8+, and CD4−CD8− T cells were assessed by flow cytometry. Results. The percentage of CD4+CD161+ T cells in RA SF was higher than RA PB, and it was positively correlated with DAS28, erythrocyte sedimentation rate (ESR, and C-reactive protein (CRP. CD4−CD8−CD161+ T cell percentage was decreased in RA PB and was further reduced in RA SF, and its level in SF was inversely correlated with DAS28, ESR, and CRP. However, CD8+CD161+ T cell percentage was neither changed in RA PB and SF nor correlated with disease activity indices. Conclusion. An increased CD4+CD161+ T cell percentage and a decreased CD4−CD8−CD161+ T cell percentage are present in RA SF and are associated with disease activity, and the accumulation of CD4+CD161+ T cells in SF may contribute to the local inflammation of RA.

  13. A novel SIV gag-specific CD4(+)T-cell clone suppresses SIVmac239 replication in CD4(+)T cells revealing the interplay between antiviral effector cells and their infected targets.

    Science.gov (United States)

    Ayala, Victor I; Trivett, Matthew T; Coren, Lori V; Jain, Sumiti; Bohn, Patrick S; Wiseman, Roger W; O'Connor, David H; Ohlen, Claes; Ott, David E

    2016-06-01

    To study CD4(+)T-cell suppression of AIDS virus replication, we isolated nine rhesus macaque SIVGag-specific CD4(+)T-cell clones. One responding clone, Gag68, produced a typical cytotoxic CD8(+)T-cell response: induction of intracellular IFN-γ, MIP-1α, MIP-1β, and CD107a degranulation. Gag68 effectively suppressed the spread of SIVmac239 in CD4(+)T cells with a corresponding reduction of infected Gag68 effector cells, suggesting that CD4(+)effectors need to suppress their own infection in addition to their targets to be effective. Gag68 TCR cloning and gene transfer into CD4(+)T cells enabled additional experiments with this unique specificity after the original clone senesced. Our data supports the idea that CD4(+)T cells can directly limit AIDS virus spread in T cells. Furthermore, Gag68 TCR transfer into CD4(+)T-cell clones with differing properties holds promise to better understand the suppressive effector mechanisms used by this important component of the antiviral response using the rhesus macaque model. PMID:27017056

  14. Evaluation of PIMA Point-of-care CD4 Analyzer in Yunnan, China

    Institute of Scientific and Technical Information of China (English)

    Jun Liang; Song Duan; Yan-Ling Ma; Ji-Bao Wang; Ying-Zhen Su; Hui Zhang; Chin-Yih Qu

    2015-01-01

    Background:CD4 count is used to determine antiretroviral therapy (ART) eligibility.In China,flow cytometers are mostly located in urban areas with limited access by patients residing in remote areas.In an attempt to address this issue,we conducted a study to validate the performance ofAlere PIMA point-of-care CD4 analyzer.Methods:Venous and finger-prick blood specimens were collected from HIV-positive participants from two voluntary counseling and testing sites in Yunnan Province.Both venous and finger-prick blood specimens were tested with the PIMA analyzer.Venous blood specimens tested with the Becton Dickinson FACSCalibur were used as a reference.Results:Venous specimens from 396 and finger-prick specimens from 387 persons were available for analysis.CD4 counts by PIMA correlated well with those from FACSCalibur with an R2 of 0.91 for venous blood and 0.81 for finger-prick blood.Compared to FACSCalibur,the PIMA analyzer yielded lower counts with a mean bias of-47.0 cells/μl (limit of agreement,[LOA]:-204-110 cells/μl) for venous blood and-71.0 cells/μl (LOA:-295-153 cells/μ1) for finger-prick blood.For a CD4 threshold of 350 cells/μl,the positive predictive value (PPV) of PIMA was 84.2% and 75.7% and the negative predictive value (NPV) was 97.6% and 95.8% for venous and finger-prick blood,respectively.For an ART threshold of 500 cells/μl,the corresponding PPV was 90.3% and 84.0% and NPV was 94.3% and 93.4%,respectively.Conclusions:CD4 counting using venous blood with PIMA analyzers is a feasible alternative to a large flow cytometer to determine ART eligibility.

  15. Immunotherapy With IL-10 and IFN-γ Producing CD4 Effector Cells Modulate “Natural” And “Inducible” CD4 TReg Cell Subpopulation Levels: Observations In Four Cases Of Patients With Ovarian Cancer

    OpenAIRE

    Dobrzanski, Mark J.; Rewers-Felkins, Kathleen A.; Samad, Khaliquzzaman A.; Quinlin, Imelda S.; Phillips, Catherine A.; Robinson, William; Dobrzanski, David J.; Wright, Stephen E.

    2011-01-01

    Adoptive T cell therapy for cancer patients optimally requires participation of CD4 T cells. In this phase I/II study, we assessed the therapeutic effects of adoptively transferred IL-10 and IFN-γ-producing CD4 effector cells in patients with recurrent ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that 3 monthly treatment cycles of autologous T cell restimulation and local intraperitoneal re-infusion modulated T cell mediated immune responses th...

  16. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination

    OpenAIRE

    Casares, N. (Noelia); L. Arribillaga; Sarobe, P.; Dotor, J. (Javier); Lopez-Diaz-de-Cerio, A. (Ascensión); Melero, I; Lasarte, J.J. (Juan José)

    2003-01-01

    CD25(+) regulatory T (T reg) cells suppress the activation/proliferation of other CD4(+) or CD8(+) T cells in vitro. Also, down-regulation of CD25(+) T reg cells enhance antitumor immune responses. In this study, we show that depletion of CD25(+) T reg cells allows the host to induce both CD4(+) and CD8(+) antitumoral responses following tumor challenge. Simultaneous depletion of CD25(+) and CD8(+) cells, as well as adoptive transfer experiments, revealed that tumor-specific CD4(+) T cells, w...

  17. Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3

    OpenAIRE

    Chen, Wanjun; Jin, Wenwen; Hardegen, Neil; Lei, Ke-Jian; Li, Li; Marinos, Nancy; McGrady, George; Wahl, Sharon M.

    2003-01-01

    CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25− naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transformin...

  18. CD4+CD25+调节性T细胞在支气管哮喘中的研究进展%The researches on CD4+CD25+ Treg in bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    李营营; 冯学斌

    2007-01-01

    CD4+CD25+调节性T细胞(CD4+CD25+Treg)是一种表型和功能特异的T细胞亚群,它在抑制自身免疫性疾病的发生,诱导机体免疫耐受机制中发挥着重要作用.研究CD4+CD25+Treg在支气管哮喘中的功能机制,对阐明哮喘的发病机制及探索疾病免疫治疗方面有重要意义.

  19. Analysis of the In Vivo Turnover of CD4+ T-Cell Subsets in Chronically SIV-Infected Sooty Mangabeys.

    Science.gov (United States)

    Ortiz, Alexandra M; Carnathan, Diane G; Yu, Joana; Sheehan, Katherine M; Kim, Peter; Reynaldi, Arnold; Vanderford, Thomas H; Klatt, Nichole R; Brenchley, Jason M; Davenport, Miles P; Silvestri, Guido

    2016-01-01

    Aberrant turnover of memory CD4+ T-cells is central to Acquired Immunodeficiency Syndrome (AIDS) progression. Understanding the relationship between the turnover of CD4+ subsets and immunological homeostasis during simian immunodeficiency virus (SIV) infection in natural hosts may provide insight into mechanisms of immune regulation that may serve as models for therapeutic intervention in Human Immunodeficiency Virus (HIV)-infected persons. Sooty mangabeys (SMs) have naturally evolved with SIV to avoid AIDS progression while maintaining healthy peripheral CD4+ T-cell counts and thus represent a model by which therapeutic interventions for AIDS progression might be elucidated. To assess the relationship between the turnover of CD4+ subsets and immunological homeostasis during SIV infection in non-progressive hosts, we treated 6 SIV-uninfected and 9 SIV-infected SMs with 2'-bromo-5'-deoxyuridine (BrdU) for 14 days and longitudinally assessed CD4+ T-cell subset turnover by polychromatic flow cytometry. We observed that, in SIV-infected SMs, turnover of CD4+ T-cell naïve and central, transitional, and effector memory subsets is comparable to that in uninfected animals. Comparable turnover of CD4+ T-cell subsets irrespective of SIV-infection status likely contributes to the lack of aberrant immune activation and disease progression observed after infection in non-progressive hosts. PMID:27227993

  20. Analysis of the In Vivo Turnover of CD4+ T-Cell Subsets in Chronically SIV-Infected Sooty Mangabeys.

    Directory of Open Access Journals (Sweden)

    Alexandra M Ortiz

    Full Text Available Aberrant turnover of memory CD4+ T-cells is central to Acquired Immunodeficiency Syndrome (AIDS progression. Understanding the relationship between the turnover of CD4+ subsets and immunological homeostasis during simian immunodeficiency virus (SIV infection in natural hosts may provide insight into mechanisms of immune regulation that may serve as models for therapeutic intervention in Human Immunodeficiency Virus (HIV-infected persons. Sooty mangabeys (SMs have naturally evolved with SIV to avoid AIDS progression while maintaining healthy peripheral CD4+ T-cell counts and thus represent a model by which therapeutic interventions for AIDS progression might be elucidated. To assess the relationship between the turnover of CD4+ subsets and immunological homeostasis during SIV infection in non-progressive hosts, we treated 6 SIV-uninfected and 9 SIV-infected SMs with 2'-bromo-5'-deoxyuridine (BrdU for 14 days and longitudinally assessed CD4+ T-cell subset turnover by polychromatic flow cytometry. We observed that, in SIV-infected SMs, turnover of CD4+ T-cell naïve and central, transitional, and effector memory subsets is comparable to that in uninfected animals. Comparable turnover of CD4+ T-cell subsets irrespective of SIV-infection status likely contributes to the lack of aberrant immune activation and disease progression observed after infection in non-progressive hosts.

  1. CD4 decline is associated with increased risk of cardiovascular disease, cancer, and death in virally suppressed patients with HIV

    DEFF Research Database (Denmark)

    Helleberg, Marie; Kronborg, Gitte; Larsen, Carsten S; Pedersen, Gitte; Pedersen, Court; Obel, Niels; Gerstoft, Jan

    2013-01-01

    immunodeficiency virus (HIV) were followed in the Danish nationwide, population-based cohort study in the period 1995-2010 with quarterly CD4 measurements. Associations between a CD4 decline of ≥30% and cardiovascular disease, cancer, and death were analyzed using Poisson regression with date of CD4 decline as a...... time-updated variable. Results. We followed 2584 virally suppressed HIV patients for 13 369 person-years (PY; median observation time, 4.7 years). Fifty-six patients developed CD4 decline (incidence rate, 4.2/1000 PY [95% confidence interval {CI}, 3.2-5.4]). CD4 counts dropped from a median of 492...... cells/µL to 240 cells/µL. CD8, CD3, and total lymphocyte counts dropped concomitantly. No HIV-related factors, apart from treatment with didanosine, were associated with CD4 decline. The risk of cardiovascular disease, cancer, and death increased markedly ≤6 months after CD4 decline (incidence rate...

  2. Higher Frequency of CD4+CXCR5+ICOS+PD1+ T Follicular Helper Cells in Patients With Infectious Mononucleosis.

    Science.gov (United States)

    Liu, Jinlin; Zhou, Yonglie; Yu, Qinghua; Zhao, Zhao; Wang, Huan; Luo, Xiaoming; Chen, Yanxia; Zhu, Zhongliang; Chen, Guoqing; Wu, Mao; Qiu, Liannv

    2015-11-01

    Follicular helper T (Tfh) cells are recognized as a distinct CD4helper T cell subset, and mainly dysregulated in the autoimmune disease, whether it plays a role in the infectious mononucleosis (IM) diseases is unknown. In this study, we found that the CD4CXCR5 Tfh cells were not significantly changed, but the CD4CXCR5ICOS and CD4CXCR5ICOSPD1 Tfh subsets were significantly increased in the IM patients, and all these cells were significantly changed after antiviral therapy. Second, only the numbers of CD4CXCR5ICOSPD1 Tfh cells correlated with the Epstein-Barr virus (EBV) DNA load, negatively correlated with the numbers of naive B cells and amount of IL-21, and positively correlated with the numbers of plasma cells, memory B cells, and atypical lymphocytes. Third, the frequency of CD4CXCR5ICOSPD1 Tfh subset was significantly higher in lymphadenectasis or hepatosplenomegaly patients, and associated with the level of alanine aminotransferase (ALT). All together, our findings discovered this CD4CXCR5ICOSPD1 Tfh cell subset might play an important role in the pathogenesis of IM. PMID:26559315

  3. CD4 changes among virologically suppressed patients on antiretroviral therapy: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Nathan Ford

    2015-08-01

    Full Text Available Introduction: The effectiveness of antiretroviral therapy (ART is assessed by measuring CD4 cell counts and viral load. Recent studies have questioned the added value of routine CD4 cell count measures in patients who are virologically suppressed. Methods: We systematically searched three databases and two conference sites up to 31 October 2014 for studies reporting CD4 changes among patients who were on ART and virologically suppressed. No geographic, language or age restrictions were applied. Results and discussion: We identified 12 published and 1 unpublished study reporting CD4 changes among 20,297 virologically suppressed patients. The pooled proportion of patients who experienced an unexplained, confirmed CD4 decline was 0.4% (95% CI 0.2–0.6%. Results were not influenced by duration of follow-up, age, study design or region of economic development. No studies described clinical adverse events among virologically suppressed patients who experienced CD4 declines. Conclusions: The findings of this review support reducing or stopping routine CD4 monitoring for patients who are immunologically stable on ART in settings where routine viral load monitoring is provided.

  4. Scaling up antiretroviral treatment services in Karnataka, India: impact on CD4 counts of HIV-infected people.

    Directory of Open Access Journals (Sweden)

    Suresh Shastri

    Full Text Available SETTING: Twelve antiretroviral treatment centres under National AIDS Control Programme (NACP, Karnataka State, India. OBJECTIVE: For the period 2004-2011, to describe the trends in the numbers of people living with HIV (PLHIV registered for care and their median baseline CD4 counts, disaggregated by age and sex. DESIGN: Descriptive study involving analysis of routinely captured data (year of registration, age, sex, baseline CD4 count under NACP. RESULTS: 34,882 (97% of total eligible PLHIV were included in analysis. The number registered for care has increased by over 12 times during 2004-11; with increasing numbers among females. The median baseline CD4 cell count rose from 125 in 2004 to 235 in 2011--the increase was greater among females as compared to males. However, about two-thirds still presented at CD4 cell counts less than 350. CONCLUSION: We found an increasing trend of median CD4 counts among PLHIV presenting to ART centres in Karnataka, an indicator of enhanced and early access to HIV care. Equal proportion of females and higher baseline CD4 counts among them allays any fear of differential access by gender. Despite this relative success, a substantial proportion still presented at low CD4 cell counts indicating possibly delayed HIV diagnosis and delayed linkage to HIV care. Universal HIV testing at health care facilities and strengthening early access to care are required to bridge the gap.

  5. In Vivo Identification and Characterization of CD4+ Cytotoxic T Cells Induced by Virulent Brucella abortus Infection

    Science.gov (United States)

    Martirosyan, Anna; Von Bargen, Kristine; Arce Gorvel, Vilma; Zhao, Weidong; Hanniffy, Sean; Bonnardel, Johnny; Méresse, Stéphane; Gorvel, Jean-Pierre

    2013-01-01

    CD4+ T cells display a variety of helper functions necessary for an efficient adaptive immune response against bacterial invaders. This work reports the in vivo identification and characterization of murine cytotoxic CD4+ T cells (CD4+ CTL) during Brucella abortus infection. These CD4+ CTLs express granzyme B and exhibit immunophenotypic features consistent with fully differentiated T cells. They express CD25, CD44, CD62L ,CD43 molecules at their surface and produce IFN-γ. Moreover, these cells express neither the co-stimulatory molecule CD27 nor the memory T cell marker CD127. We show here that CD4+ CTLs are capable of cytolytic action against Brucella-infected antigen presenting cells (APC) but not against Mycobacterium-infected APC. Cytotoxic CD4+ T cell population appears at early stages of the infection concomitantly with high levels of IFN-γ and granzyme B expression. CD4+ CTLs represent a so far uncharacterized immune cell sub-type triggered by early immune responses upon Brucella abortus infection. PMID:24367519

  6. In vivo identification and characterization of CD4⁺ cytotoxic T cells induced by virulent Brucella abortus infection.

    Science.gov (United States)

    Martirosyan, Anna; Von Bargen, Kristine; Arce Gorvel, Vilma; Zhao, Weidong; Hanniffy, Sean; Bonnardel, Johnny; Méresse, Stéphane; Gorvel, Jean-Pierre

    2013-01-01

    CD4(+) T cells display a variety of helper functions necessary for an efficient adaptive immune response against bacterial invaders. This work reports the in vivo identification and characterization of murine cytotoxic CD4(+) T cells (CD4(+) CTL) during Brucella abortus infection. These CD4(+) CTLs express granzyme B and exhibit immunophenotypic features consistent with fully differentiated T cells. They express CD25, CD44, CD62L ,CD43 molecules at their surface and produce IFN-γ. Moreover, these cells express neither the co-stimulatory molecule CD27 nor the memory T cell marker CD127. We show here that CD4(+) CTLs are capable of cytolytic action against Brucella-infected antigen presenting cells (APC) but not against Mycobacterium-infected APC. Cytotoxic CD4(+) T cell population appears at early stages of the infection concomitantly with high levels of IFN-γ and granzyme B expression. CD4(+) CTLs represent a so far uncharacterized immune cell sub-type triggered by early immune responses upon Brucella abortus infection. PMID:24367519

  7. Antigen-Experienced CD4lo T Cells Are Linked to Deficient Contraction of the Immune Response in Autoimmune Diabetes

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    Sean Linkes

    2010-01-01

    Full Text Available Following proper activation, naïve “CD4lo” T cells differentiate into effector T cells with enhanced expression of CD4 -“CD4hi” effectors. Autoimmune diabetes-prone NOD mice display a unique set of antigen-experienced “CD4lo” T cells that persist after primary stimulation. Here, we report that a population of such cells remained after secondary and tertiary TCR stimulation and produced cytokines upon antigenic challenge. However, when NOD blasts were induced in the presence of rIL-15, the number of antigen-experienced “CD4lo” T cells was significantly reduced. Clonal contraction, mediated in part by CD95-dependent activation-induced cell death (AICD, normally regulates the accumulation of “CD4hi” effectors. Interestingly, CD95 expression was dramatically reduced on the AICD-resistant NOD “CD4lo” T cells. Thus, while autoimmune disease has often been attributed to the engagement of robust autoimmunity, we suggest that the inability to effectively contract the immune response distinguishes benign autoimmunity from progressive autoimmune diseases that are characterized by chronic T cell-mediated inflammation.

  8. Antigen presentation by small intestinal epithelial cells uniquely enhances IFN-γ secretion from CD4+ intestinal intraepithelial lymphocytes

    International Nuclear Information System (INIS)

    Highlights: •Small intestinal epithelial cells (sIECs). •sIECs are able to induce antigen specific proliferation of CD4+ IELs. •sIECs induce markedly enhanced IFN-γ secretion by CD4+ IELs. •Induction of enhanced IFN-γ secretion by sIECs is uniquely observed in CD4+ IELs. -- Abstract: Small intestinal epithelial cells (sIECs) express major histocompatibility complex class II molecules even in a normal condition, and are known to function as antigen presenting cells (APCs) at least in vitro. These findings raised the possibility that sIECs play an important role in inducing immune responses against luminal antigens, especially those of intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). We herein showed that antigenic stimulation with sIECs induced markedly greater secretion of interferon-gamma (IFN-γ) by CD4+ IELs, but not interleukin (IL)-4, IL-10 and IL-17 although the proliferative response was prominently lower than that with T cell-depleted splenic APCs. In contrast, no enhanced IFN-γ secretion by CD4+ LPLs and primed splenic CD4+ T cells was observed when stimulated with sIECs. Taken together, these results suggest that sIECs uniquely activate CD4+ IELs and induce remarkable IFN-γ secretion upon antigenic stimulation in vivo

  9. Antigen presentation by small intestinal epithelial cells uniquely enhances IFN-γ secretion from CD4{sup +} intestinal intraepithelial lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Hatano, Ryo; Yamada, Kiyoshi; Iwamoto, Taku; Maeda, Nana; Emoto, Tetsuro; Shimizu, Makoto; Totsuka, Mamoru, E-mail: atotuka@mail.ecc.u-tokyo.ac.jp

    2013-06-14

    Highlights: •Small intestinal epithelial cells (sIECs). •sIECs are able to induce antigen specific proliferation of CD4{sup +} IELs. •sIECs induce markedly enhanced IFN-γ secretion by CD4{sup +} IELs. •Induction of enhanced IFN-γ secretion by sIECs is uniquely observed in CD4{sup +} IELs. -- Abstract: Small intestinal epithelial cells (sIECs) express major histocompatibility complex class II molecules even in a normal condition, and are known to function as antigen presenting cells (APCs) at least in vitro. These findings raised the possibility that sIECs play an important role in inducing immune responses against luminal antigens, especially those of intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). We herein showed that antigenic stimulation with sIECs induced markedly greater secretion of interferon-gamma (IFN-γ) by CD4{sup +} IELs, but not interleukin (IL)-4, IL-10 and IL-17 although the proliferative response was prominently lower than that with T cell-depleted splenic APCs. In contrast, no enhanced IFN-γ secretion by CD4{sup +} LPLs and primed splenic CD4{sup +} T cells was observed when stimulated with sIECs. Taken together, these results suggest that sIECs uniquely activate CD4{sup +} IELs and induce remarkable IFN-γ secretion upon antigenic stimulation in vivo.

  10. A human recombinant Fab identifies a human immunodeficiency virus type 1-induced conformational change in cell surface-expressed CD4.

    OpenAIRE

    Bachelder, R E; Bilancieri, J; W. Lin; Letvin, N. L.

    1995-01-01

    To explore the role of the CD4 molecule in human immunodeficiency virus (HIV) infection following initial virus-CD4 binding, we have characterized CD4-specific antibodies raised by immunizing an HIV-1-infected human with human recombinant soluble CD4 (rsCD4). Fabs were selected from a human recombinant Fab library constructed from the bone marrow of this immunized individual. Here, we describe a human rsCD4-specific recombinant Fab clone selected by panning the library over complexes of human...

  11. Utility of total lymphocyte count as a surrogate marker for CD4 counts in HIV-1 infected children in Kenya

    Directory of Open Access Journals (Sweden)

    Wamalwa Dalton C

    2011-09-01

    Full Text Available Abstract Background In resource-limited settings, such as Kenya, access to CD4 testing is limited. Therefore, evaluation of less expensive laboratory diagnostics is urgently needed to diagnose immuno-suppression in children. Objectives To evaluate utility of total lymphocyte count (TLC as surrogate marker for CD4 count in HIV-infected children. Methods This was a hospital based retrospective study conducted in three HIV clinics in Kisumu and Nairobi in Kenya. TLC, CD4 count and CD4 percent data were abstracted from hospital records of 487 antiretroviral-naïve HIV-infected children aged 1 month - 12 years. Results TLC and CD4 count were positively correlated (r = 0.66, p 59 months of age (r = 0.68, p 3, age 12-35 months (CD4 count 3, and age above 59 months (CD4 count 3. WHO recommended TLC threshold values for severe immuno-suppression of 4000, 3000, 2500 and 2000 cells/mm3 for age categories 59 months had low sensitivity of 25%, 23%, 33% and 62% respectively in predicting severe immuno-suppression using CD4 count as gold standard. Raising TLC thresholds to 7000, 6000, 4500 and 3000 cells/mm3 for each of the stated age categories increased sensitivity to 71%, 64%, 56% and 86%, with positive predictive values of 85%, 61%, 37%, 68% respectively but reduced specificity to 73%, 62%, 54% and 68% with negative predictive values of 54%, 65%, 71% and 87% respectively. Conclusion TLC is positively correlated with absolute CD4 count in children but current WHO age-specific thresholds had low sensitivity to identify severely immunosuppressed Kenyan children. Sensitivity and therefore utility of TLC to identify immuno-suppressed children may be improved by raising the TLC cut off levels across the various age categories.

  12. Impact of pharmaceutical care interventions on the CD4+ lymphocytes counts (therapeutic outcome of patients on antiretroviral drugs

    Directory of Open Access Journals (Sweden)

    Ezeudo Ewuziem Nwaozuzu

    2012-12-01

    Full Text Available CD4 count and viral load determine the progression of HIV infection. HIV actively infects and destroys CD4 cells. High viral load results in higher transmission risk and is also a sign of more severe disease. Measurements of CD4 counts can be used as an indirect means of estimating HIV viral load and as such determine disease progression and/or therapeutic outcome of antiretroviral therapy. Pharmaceutical care (PC has been shown to improve the outcome of drug therapy in many disease conditions. HIV/AIDS is one of the disease conditions that are fraught with many problems that can benefit from this new emphasis of pharmacy practice also known as ‘pharmacists care’. This study is designed to evaluate the impact of pharmaceutical care activities on the CD4 cell counts of HIV/AIDS patients receiving antiretroviral drugs. The components of the American society of health-system pharmacists (ASHP guidelines on ‘standardized method for pharmaceutical care’ was used as a data collection instrument to evaluate, document and intervene and re-evaluate the antiretroviral therapy of about one thousand four hundred and seventy three (1,473 patients. The results showed that that 55.2% of the patients recorded significant increases in their CD4 cells count, 14.1% of them maintained their pre - intervention CD4 cells count while 10.3% of them recorded decreases in their CD4 cell count. However, in 20.4% of the patients the CD4 cell counts could not be determined. The study showed that pharmacists’ interventions in antiretroviral drug therapy through Pharmaceutical care can significantly improve the CD4 cells counts of patients receiving antiretroviral drugs hence therapeutic outcome of antiretroviral drug therapy.

  13. How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules?

    Directory of Open Access Journals (Sweden)

    Ole Audun Werner Haabeth

    2014-04-01

    Full Text Available CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor specific antigen by host antigen presenting cells (APCs appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315, where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

  14. Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells

    Science.gov (United States)

    Church, Sarah E; Jensen, Shawn M; Antony, Paul A; Restifo, Nicholas P; Fox, Bernard A

    2014-01-01

    Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4+ T cells enhance CD8+ T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4+ transgenic T cells-CD4+ T cells and pmel-CD8+ T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8+ T cells with tumor-specific cytokine expression. When combined with CD4+ T cells, transfer of total (naïve and effector) or effector CD8+ T cells were highly effective, suggesting CD4+ T cells can help mediate therapeutic effects by maintaining function of activated CD8+ T cells. In addition, CD4+ T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8+ T cells recovered from mice treated with both CD8+ and CD4+ T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4+ T cells help reduce CD8+ T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4+ and CD8+ T cells for treatment of patients with cancer. PMID:24114780

  15. Sequential Dysfunction and Progressive Depletion of Candida albicans-Specific CD4 T Cell Response in HIV-1 Infection

    Science.gov (United States)

    Liu, Fengliang; Fan, Xiuzhen; Auclair, Sarah; Ferguson, Monique; Sun, Jiaren; Soong, Lynn; Hou, Wei; Redfield, Robert R.; Birx, Deborah L.; Ratto-Kim, Silvia; Robb, Merlin L.; Kim, Jerome H.; Michael, Nelson L.; Hu, Haitao

    2016-01-01

    Loss of immune control over opportunistic infections can occur at different stages of HIV-1 (HIV) disease, among which mucosal candidiasis caused by the fungal pathogen Candida albicans (C. albicans) is one of the early and common manifestations in HIV-infected human subjects. The underlying immunological basis is not well defined. We have previously shown that compared to cytomegalovirus (CMV)-specific CD4 cells, C. albicans-specific CD4 T cells are highly permissive to HIV in vitro. Here, based on an antiretroviral treatment (ART) naïve HIV infection cohort (RV21), we investigated longitudinally the impact of HIV on C. albicans- and CMV-specific CD4 T-cell immunity in vivo. We found a sequential dysfunction and preferential depletion for C. albicans-specific CD4 T cell response during progressive HIV infection. Compared to Th1 (IFN-γ, MIP-1β) functional subsets, the Th17 functional subsets (IL-17, IL-22) of C. albicans-specific CD4 T cells were more permissive to HIV in vitro and impaired earlier in HIV-infected subjects. Infection history analysis showed that C. albicans-specific CD4 T cells were more susceptible to HIV in vivo, harboring modestly but significantly higher levels of HIV DNA, than CMV-specific CD4 T cells. Longitudinal analysis of HIV-infected individuals with ongoing CD4 depletion demonstrated that C. albicans-specific CD4 T-cell response was preferentially and progressively depleted. Taken together, these data suggest a potential mechanism for earlier loss of immune control over mucosal candidiasis in HIV-infected patients and provide new insights into pathogen-specific immune failure in AIDS pathogenesis. PMID:27280548

  16. CD4(+CD25(-Nrp1(+ T cells synergize with rapamycin to prevent murine cardiac allorejection in immunocompetent recipients.

    Directory of Open Access Journals (Sweden)

    Qing Yuan

    Full Text Available Besides CD4(+CD25(+Foxp3(+ regulatory T cells (Tregs, other immunosuppressive T cells also participated in the regulation of immune tolerance. Reportedly, neuropilin-1 (Nrp1 might be one of the molecules by which regulatory cells exert their suppressive effects. Indeed, CD4(+CD25(-Nrp1(+ T cells exhibit potent suppressive function in autoimmune inflammatory responses. Here we investigated the specific role of CD4(+CD25(-Nrp1(+ T cells in the setting of the transplant immune response. Through MLR assays, we found that CD4(+CD25(-Nrp1(+ T cells suppressed the proliferation of naive CD4(+CD25(- T cells activated by allogeneic antigen-stimulation. Adoptive transfer of CD4(+CD25(-Nrp1(+ T cells synergized with rapamycin to induce long-term graft survival in fully MHC-mismatched murine heart transplantation, which was associated with decreased IFN-γ, IL-17 and increased IL-10, TGF-β, Foxp3 and Nrp1 expression in the grafts. Importantly, our data indicated that CD4(+CD25(-Nrp1(+ T cell transfer augments the accumulation of Tregs in the recipient, and creates conditions that favored induction of hyporesponsiveness of the T effector cells. In conclusion, this translational study indicates the possible therapeutic potential of CD4(+CD25(-Nrp1(+ T cells in preventing allorejection. CD4(+Nrp1(+ T cells might therefore be used in bulk as a population of immunosuppressive cells with more beneficial properties concerning ex vivo isolation as compared to Foxp3(+ Tregs.

  17. HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells.

    Science.gov (United States)

    Riou, Catherine; Strickland, Natalie; Soares, Andreia P; Corleis, Björn; Kwon, Douglas S; Wherry, E John; Wilkinson, Robert J; Burgers, Wendy A

    2016-04-01

    HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-α (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets. PMID:26927799

  18. Impact of long-term viral suppression in CD4+ recovery of HIV-children on Highly Active Antiretroviral Therapy

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    Gurbindo-Gutierrez Dolores

    2006-01-01

    Full Text Available Abstract Background The effects of HAART may differ between children and adults because children have a developing immune system, and the long-term immunological outcome in HIV-infected children on HAART is not well-known. A major aim of our study was to determine CD4+ evolution associated with long-term VL control during 4 years of observation on HAART. Methods We carried out a retrospective study on a cohort of 160 vertically HIV-infected children. It was carried out from 1996 to 2004 in six large Spanish pediatric referral hospitals. We compared 33 children who had long-term VL suppression (VL ≤400 copies/ml in the first 12 months of follow-up and maintained that level throughout follow-up (Responders-group, and 127 children with persistently detectable VL in spite of ART switches (Non-Responders-group. Results We observed a quick initial and significant increase in CD4+ counts from the baseline to 12 months on HAART in both groups (p Non-Responders group sustained CD4+ increases and most of these children maintained high CD4+ level counts (≥25%. The Non-Responders group reached a plateau between 26% and 27% CD4+ at the first 12 months of follow-up that remained stable during the following 3 years. However, the Responders group reached a plateau between 30% and 32% CD4+ at 24, 36 and 48 months of follow-up. We found that the Responders group had higher CD4+ count values and higher percentages of children with CD4+ ≥25% than the Non-Responders group (p Conclusion Long-term VL suppression in turn induces large beneficial effects in immunological responses. However, it is not indispensable to recover CD4+ levels.

  19. Adhesion versus coreceptor function of CD4 and CD8: role of the cytoplasmic tail in coreceptor activity.

    OpenAIRE

    Miceli, M C; Von Hoegen, P.; Parnes, J R

    1991-01-01

    CD4 and CD8 play an important role in T-cell recognition and activation; however, their mechanisms of action are not well understood. We compare the effects of expressing CD4 and CD8 alpha either individually or together in a class II-restricted T-cell hybridoma. We also compare the effects of expressing truncated forms of CD4 or CD8 alpha that do not have a cytoplasmic tail and thus do not associate with the T-cell-specific tyrosine kinase p56lck, which has been implicated in T-cell activati...

  20. Identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade#

    OpenAIRE

    Pauken, Kristen E.; Nelson, Christine E; Martinov, Tijana; Spanier, Justin A.; Heffernan, James R; Sahli, Nathanael L; Quarnstrom, Clare F; Osum, Kevin C; Schenkel, Jason M.; Jenkins, Marc K.; Blazar, Bruce R; Vezys, Vaiva; Fife, Brian T.

    2015-01-01

    Programmed Death (PD)-1 promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD-L1 regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in Type 1 Diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additiona...

  1. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite

    OpenAIRE

    Combe, Crescent L; Moretto, Magali M.; Schwartzman, Joseph D; Gigley, Jason P.; Bzik, David J.; Khan, Imtiaz A.

    2006-01-01

    IFN-γ-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-γ-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15−/− mice reversed inhibition of gu...

  2. Role of Circulating CD4+ CD25high Foxp3+ Regulatory T-Cells in Paediatric Asthma

    OpenAIRE

    Ensaf Khalil Mohammed*, Zeinab Farag Asheiba

    2011-01-01

    Background: The role of T-Helper 2 (Th2) cells in the pathogenesis of allergy and asthma has been well described. However, the immunologic mechanisms that down modulate and protect against the development of these disorders are poorly characterized. A spectrum of CD4+ T cells, including, FOXP3-positive CD4+CD25+ T regulatory cells (Tregs) might play a critical role in regulating these diseases. Objective: To investigate the role of CD4+CD25high FoxP3 Tregs in the pathogenesis of pediatric ast...

  3. Role of Circulating CD4+ CD25high Foxp3+ Regulatory T-Cells in Paediatric Asthma

    Directory of Open Access Journals (Sweden)

    Ensaf Khalil Mohammed*, Zeinab Farag Asheiba

    2011-04-01

    Full Text Available Background: The role of T-Helper 2 (Th2 cells in the pathogenesis of allergy and asthma has been well described. However, the immunologic mechanisms that down modulate and protect against the development of these disorders are poorly characterized. A spectrum of CD4+ T cells, including, FOXP3-positive CD4+CD25+ T regulatory cells (Tregs might play a critical role in regulating these diseases. Objective: To investigate the role of CD4+CD25high FoxP3 Tregs in the pathogenesis of pediatric asthma. Methods: The study included 24 asthmatic children, 12 had mild intermittent asthma and 12 were of severe persistent asthma . In addition, 12 healthy subjects were used as controls. All patients were subjected to clinical examination and laboratory investigations including complete blood count with differential leucocytic and absolute eosinophilic count, serum total IgE level by ELIZA and flow cytometry was used to study the frequency of Tregs in peripheral blood lymphocytes of all studied groups using specific markers: cell-surface CD25 and CD4 expression and cytoplasmic FoxP3 expression. Results: It was noticed a significant decrease in CD4+CD25+ % and CD4+CD25 high % in both mild intermittent cases and severe persistent asthmatic patients when compared to healthy controls. FoxP3 expression in Tregs was significantly lower in CD4+CD25high T-cells of mild asthmatic patients when compared to control group. While the FoxP3 expression in Tregs was non- significantly lower in CD4+CD25high T-cells of severe asthmatic patients .Tregs cells % was correlated significantly with mild asthma .While it did not show correlation with severe asthma . An inverse correlation between FoxP3 protein expression was revealed within CD4+CD25high T-cells and total serum IgE when analyzed for all subjects. However, when correlation analysis was performed in each studied group separately, no significant correlation was found between FoxP3 expression and total serum IgE levels and

  4. Selective Priming and Expansion of Antigen-Specific Foxp3- CD4+ T cells during Listeria monocytogenes infection

    OpenAIRE

    Ertelt, James M.; Rowe, Jared H.; Johanns, Tanner M.; Lai, Joseph C.; McLachlan, James B.; Way, Sing Sing

    2009-01-01

    The Foxp3-expressing subset of regulatory CD4+ T cells have defined antigen-specificity and play essential roles in maintaining peripheral tolerance by suppressing the activation of self-reactive T cells. Similarly during chronic infection, pathogen-specific Foxp3-expressing CD4+ T cells expand and actively suppress pathogen-specific effector T cells. Herein, we used MHC class II tetramers and Foxp3gfp knock-in mice to track the kinetics and magnitude whereby pathogen-specific Foxp3+CD4+ and ...

  5. FOXP3 Inhibits HIV-1 Infection of CD4 T-cells via Inhibition of LTR Transcriptional Activity

    OpenAIRE

    Selliah, Nithianandan; Zhang, Mingce; White, Sara; Zoltick, Philip; Sawaya, Bassel E.; Finkel, Terri H.; Cron, Randy Q

    2008-01-01

    FOXP3 is a necessary transcription factor for the development and function of CD4+ regulatory T-cells (Tregs). The role of Tregs in HIV-1 infection remains unclear. Here, we show expression of FOXP3 in primary human CD4 T-cells significantly inhibits HIV-1 infection. Since FOXP3 inhibits NFAT activity, and NFAT proteins contribute to HIV-1 transcription, we explore a transcriptional repressive function of HIV-1 LTR by FOXP3. Over-expression of FOXP3 in primary CD4 T-cells inhibits wild-type H...

  6. CD4+ T-cell lines used to evaluate a Mycobacterium avium subsp. paratuberculosis (MAP) peptide vaccine

    OpenAIRE

    Lybeck, Kari; Sjurseth, Siri K.; Al-Touama, Zainab; Melvang, Heidi Mikkelsen; Aagaard, Claus; Lundegaard, Claus; Jungersen, Gregers; Andersen, Peter; Olsen, Ingrid; Tollefsen, Stig

    2015-01-01

    The aim of the study was to establish a protocol for generation of MAP-specific T-cell lines and to use these lines for evaluation of a peptide vaccine.A protocol for culturing T-cell lines from peripheral blood of goats naturally infected with MAP was established. CD4+ T cells were positively selected using an anti CD4 mAb and Dynabeads. Sorted CD4+ cells were cultivated with purified protein derivative from MAP (PPDj) or E. coli sonicate, IL-2, and IL-15. After two cultivation cycles, T cel...

  7. Biological features of intrahepatic CD4+CD25+ T cells in the naturally tolerance of rat liver transplantation

    Institute of Scientific and Technical Information of China (English)

    LU Ling; ZHANG Feng; PU Liyong; YAO Aihua; YU Yue; SUN Beicheng; LI Guoqiang

    2007-01-01

    The biological features of intrahepatic CD4+CD25+ T regulatory cells in the naturally tolerance of rat liver transplantation were explored.Orthotopic liver transplantation was performed in two allogeneic rat strain combinations,one with fatal immunosuppression despite a complete major histocompatibility complex mismatch.The subjects were divided into three groups according to different donors and recipients [Tolerance group:LEW-to-DA;Rejection group:DA-to-LEW;Syngegnic group(control group):DAto-DA].The proportion of intrahepatic CD4+CD25+ T cells from three groups was determined by flow cytometry(FCM)in different time.The intrahepaitc CD4+CD25+ T cells were isolated by magnetic activated cell sorting(MACS)method and identified by FCM.The Foxp3 mRNA was detected by reverse transcriptase polymerase chain reaction(RT-PCR).And their suppression on the proliferation of CD4+CD25- T effector cells was analyzed by cell proliferation assay in vitro.Beginning immediately after transplantation,the proportion of Treg cells increased over time in both allogeneic groups but was significantly greater in the Rejection group.The proportion of Treg cells declined after day 5,and such reduction was more dramatic in the Rejection group than in the Tolerance group.Animals in the Tolerance group showed a second increase in the proportion after day 14.Intrahepatic CD4+CD25+T cells isolated from spontaneous tolerance models inhibited the proliferation of mixed lymphocyte reaction.The purity of CD4+CD25+ T cells sorted by MACS was 86%-93%.The CD4+CD25+ T cells could specifically express the Foxp3 gene compared with CD4+CD25- T cells.In vitro,the spleen cells from LEW rats can irritate the proliferation of CD4+CD25+ T cells more obviously than the syngegnic spleen cells.CD4+CD25+ Tr cells could suppress the proliferation of CD4+CD25- T cells,but the inhibition was reversed by exogenous IL-2(200 U/mL).The CD4+CD25+ T regulatory cells specifically express the Foxp3 gene,which may play an

  8. Distinct functions of the transcription factors Gata3 and ThPOK during intrathymic CD4 T cell differentiation*

    OpenAIRE

    Wang, Lie; Wildt, Kathryn F.; Zhu, Jinfang; Zhang, Xianyu; Feigenbaum, Lionel; Tessarollo, Lino; Paul, William E.; Fowlkes, B.J.; Bosselut, Rémy

    2008-01-01

    The transcription factors Gata3 and Zbtb7b are required for intrathymic CD4 T cell differentiation, but their precise roles in this process remain unclear. Here we show that, contrary to previous findings, Gata3 disruption blocked CD4 T cell lineage differentiation before CD4 lineage commitment, and in some contexts permitted ‘redirection’ of MHC class II-restricted thymocytes into the CD8 lineage. We found that Gata3 promotes Zbtb7b expression, and binds within a region of the Zbtb7b locus e...

  9. The use of anti-CD4 antibodies and down-regulatory mechanism of CD4 antigen in Th1/Th2 polarization detection%CD4单抗选择对于流式细胞术分析Th1/Th2极化的有效性评价

    Institute of Scientific and Technical Information of China (English)

    严茹红; 张萍; 朱雪明

    2007-01-01

    选择13B8.2和S3.5两株商品化的CD4单克隆抗体用于Th1/Th2极化的流式细胞术评价,分析PMA、Ionomycin和BFA单独或联合作用于外周血CD4抗原表达水平的变化,以确定Th1/Th2极化评价时有效的CD4设门单抗,并试图揭示CD4抗原降调的机制.结果表明,13B8.2可作为CD4的设门单抗. PMA和Ionomycin联合刺激会导致外周血CD4抗原的明显降低,而PMA单独刺激不能,且BFA与PMA和Iononmycin同时加入外周血中可部分抑制PMA和Ionomycin刺激引起的CD4抗原内吞和降解.

  10. CD4(+)/CD8(+) T-lymphocyte Ratio: Effects of Rehydration before Exercise in Dehydrated Men

    Science.gov (United States)

    Greenleaf, John E.; Jackson, Catherine G. R.; Lawless, Desales

    1995-01-01

    Effects of fluid ingestion on CD4+/CD8+ T-lymphocyte cell ratios were measured in four dehydrated men (ages 30-46 yr) before and after 70 min of supine submaximal (71 % VO(sub 2max) lower extremity cycle exercise. Just before exercise, Evans blue dye was injected for measurement of plasma volume. The subjects then drank one of six fluid formulations (12 ml/kg) in 3-4 min. All six mean post-hydration (pre-exercise) CD4+/CD8+ ratios (Becton-Dickinson Fluorescence Activated Cell Sorter and FACScan Consort-30 software program were below the normal range of 1.2-1.5; mean (+/- SE) and range were 0.77 +/- 0.12 and 0.39-1.15, respectively. The post-exercise ratios increased: mean = 1.36 =/- 0.15 (P less than 0.05) and range = 0.98-1.98. Regression of mean CD4+/CD8+ ratios on mean plasma osmolality resulted in pre- and post-exercise correlation coefficients of -0.76 (P less than 0.10) and -0.92 (P less than 0.01), respectively. The decreased pre-exercise ratios (after drinking) were probably not caused by the Evans blue dye but appeared to be associated more with the stress (osmotic) of dehydration. The increased post-exercise ratios to normal levels accompanied the rehydration and were not due to the varied electrolyte and osmotic concentrations of the ingested fluids or to the varied vascular volume shifts during exercise. Thus, the level of subject hydration and plasma osmotality may be factors involved in the mechanism of immune system modulation induced by exercise.

  11. Comparison of oral manifestations with CD4 count in HIV-infected patients

    Directory of Open Access Journals (Sweden)

    Subodh Arun Sontakke

    2011-01-01

    Full Text Available Aim and Objective: This study was carried out with the primary aim of correlating oral changes and general changes of HIV-infected patients with their CD4 count. Materials and Methods: 124 patients were selected, and after taking their informed consent, they were subjected to detailed history taking and thorough clinical examination. Specific oral lesions and general physical changes were recorded. Every patient was subjected to laboratory investigation for CD4 count. All these findings were tabulated. The clinical observation and laboratory findings were subjected to critical analysis and correlated. Statistical test, i.e. Student′s " t" test, was applied and objective conclusions were drawn. Result: Out of 124 patients, 40 had oral candidiasis, 6 had oral hairy leukoplakia, 12 had periodontal disease, 20 had xerostomia, 30 had melanin pigmentation, while 4 had HSV2, and atypical ulceration. Out of 40 patients with oral candidiasis, 28 patients had CD4 count 500 cell/mm 3 . Oral hairy leukoplakia occurred in equal proportions in group A and B. These periodontal diseases were more commonly in group B; xerostomia and melanin pigmentation was equally seen in group A and B. Conclusion: Oral candidiasis, oral hairy leukoplakia, linear gingival erythema, necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis are specific oral indicators which will definitely suggest to the dental surgeon that the disease is running a rapid downhill course and due to this the oral physician is in a position to raise a suspicion and alert the general physician regarding the declining immune status of patient.

  12. Specific CD4+ T-Cell Reactivity and Cytokine Release in Different Clinical Presentations of Leptospirosis.

    Science.gov (United States)

    Volz, Magdalena Sarah; Moos, Verena; Allers, Kristina; Luge, Enno; Mayer-Scholl, Anne; Nöckler, Karsten; Loddenkemper, Christoph; Jansen, Andreas; Schneider, Thomas

    2015-12-01

    Clinical manifestations of leptospirosis are highly variable: from asymptomatic to severe and potentially fatal. The outcome of the disease is usually determined in the immunological phase, beginning in the second week of symptoms. The underlying mechanisms, predictive factors, and individual immune responses that contribute to clinical variations are not well understood. The aim of this study was to determine the specifics of CD4(+) T-cell reactivity and cytokine release after stimulation with leptospiral antigens in patients with leptospirosis of different disease severities (patients with mild and severe symptoms) and in control subjects (with and without proven exposure to Leptospira). Whole-blood specimens were stimulated with Leptospira antigens in vitro. Subsequently, intracellular staining of cytokines was performed, and flow cytometry was used to assess the expression of CD40 ligand (CD40L) and the production of gamma interferon (IFN-γ), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-α) by CD4(+) T cells. The production of inflammatory cytokines such as TNF-α by CD4(+) T cells after stimulation with leptospiral antigens was highest in patients with severe disease. In contrast, the ratio of IL-10 production to TNF-α production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-α may be useful markers of the severity of the immunological phase of leptospirosis. IL-10 production by T cells after antigen-specific stimulation may indicate a more successful downregulation of the inflammatory response and may contribute to an asymptomatic course of the disease. PMID:26491036

  13. The HIV-1 gp120/V3 modifies the response of uninfected CD4 T cells to antigen presentation: mapping of the specific transcriptional signature

    Directory of Open Access Journals (Sweden)

    Spandidos Demetrios A

    2011-09-01

    Full Text Available Abstract Background The asymptomatic phase of HIV-1 infection is characterized by a progressive depletion of uninfected peripheral effector/memory CD4+ T cells that subsequently leads to immune dysfunction and AIDS symptoms. We have previously demonstrated that the presence of specific gp120/V3 peptides during antigen presentation can modify the activation of normal T-cells leading to altered immune function. The aim of the present study was to map the specific transcriptional profile invoked by an HIV-1/V3 epitope in uninfected T cells during antigen presentation. Methods We exposed primary human peripheral blood monocytes to V3 lipopeptides using a liposome delivery system followed by a superantigen-mediated antigen presentation system. We then evaluated the changes in the T-cell transcriptional profile using oligonucleotide microarrays and performed Ingenuity Pathway Analysis (IPA and DAVID analysis. The results were validated using realtime PCR, FACS, Western blotting and immunofluorescence. Results Our results revealed that the most highly modulated transcripts could almost entirely be categorized as related to the cell cycle or transcriptional regulation. The most statistically significant enriched categories and networks identified by IPA were associated with cell cycle, gene expression, immune response, infection mechanisms, cellular growth, proliferation and antigen presentation. Canonical pathways involved in energy and cell cycle regulation, and in the co-activation of T cells were also enriched. Conclusions Taken together, these results document a distinct transcriptional profile invoked by the HIV-1/V3 epitope. These data could be invaluable to determine the underlying mechanism by which HIV-1 epitopes interfere with uninfected CD4+ T-cell function causing hyper proliferation and AICD.

  14. Differential influence of the tumour-specific non-human sialic acid containing GM3 ganglioside on CD4+CD25- effector and naturally occurring CD4+CD25+ regulatory T cells function.

    Science.gov (United States)

    de León, Joel; Fernández, Audry; Clavell, Marilyn; Labrada, Mayrel; Bebelagua, Yanin; Mesa, Circe; Fernández, Luis E

    2008-04-01

    Increasing evidences suggest that the aberrant expression of certain gangliosides on malignant cells could affect host's anti-tumour-specific immune responses. We have recently documented the relevance of the N-glycolylated variant of GM3 ganglioside (NGcGM3), a tumour-specific non-human sialic acid containing ganglioside, for tumour progression. However, evidences about the implication of host's immunity in NGcGM3-promoted cancer progression had not been obtained previously. In this work, we compared tumour growth of X63 myeloma cells pre-treated or not with an inhibitor of the glucosylceramide synthase enzyme, in wild or CD4+ T cell-depleted BALB/c mice. Results clearly showed a relationship between the agonistic effect of NGcGM3 in tumour growth and the presence of CD4+ T lymphocytes. For the first time, a description of a ganglioside-differential effect over purified CD4+CD25- and naturally occurring regulatory CD4+CD25+ T cells is provided. While NGcGM3 similarly down-modulated the CD4 expression in both cell populations, the inhibitory capacity of the CD4+CD25+ lymphocytes and their proliferation, induced by an anti-CD3 mAb and IL2, were not modified. In a different fashion, a reduction in proliferative capacity and a noteworthy secretion of anti-inflammatory cytokines were detected when CD4+CD25- T cells were cultured in the presence of NGcGM3. Considering the relevance of dendritic cells (DC) on primary activation of T cells, the effect of NGcGM3 over DC differentiation and TLR4-mediated maturation was also assessed. Our results indicate that NGcGM3 contributes to cancer progression mainly by influencing DC and CD4+CD25- T lymphocyte functions, rather than increasing the inhibitory capacity of naturally occurring regulatory T cells. PMID:18310617

  15. CD4+CD25+调节性T细胞及其分子标记物与支气管哮喘%CD4+CD25+regulatory T cell and its molecular marker with bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    马祥; 毛辉; 梁宗安

    2009-01-01

    CD4+CD25+regulatory T cells are a kind of lymphocytes characterized by immune inhibition and immune inability,FOXP3 is a specific molecular marker of CD4+CD25+regulatory T cells,and critical for the generation,peripheral expression and function of CD4+CD25+regulatory T cells.In recent years,a series of studies showed that CD4+CD25+regulatory T cells interfere with the development and progression of bronchial asthma,the intervention of regulatory T cell and its relative genes may offer a novel therapeutic strategy for bronchial asthma.%CD4+CD25+调节性T细胞是一类以免疫抑制和免疫无能为特征的淋巴细胞群,FOXP3是CD4+CD25+调节性T细胞一个特征性的分子标志物,并且对CD4+CD25+调节性T细胞的发育、外周表达和功能维持有着关键性的作用.近年来,多项研究显示CD4+CD25+调节性T细胞参与并影响了支气管哮喘的发生、发展过程,对调节性T细胞或其相关基因的干预也许会成为支气管哮喘治疗的新方向.

  16. SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

    Directory of Open Access Journals (Sweden)

    Shravan Madireddi

    Full Text Available Tumors convert conventional CD4(+ T cells into induced CD4(+CD25(+FoxP3(+ T regulatory (iTreg cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4(+ T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4(+and CD8(+ T effector (Teff cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our knowledge, that signaling through 4-1BB inhibits antigen- and TGF-β-driven conversion of naïve CD4(+FoxP3(- T cells into iTreg cells via stimulation of IFN-γ production by CD4(+FoxP3(- T cells. Importantly, treatment with SA-4-1BBL blocked the conversion of CD4(+FoxP3(- T cells into Treg cells by EG.7 tumors. Taken together with our previous studies, these results show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i inhibiting the conversion of CD4(+FoxP3(- T cells into iTreg cells and ii endowing Teff cells refractory to inhibition by Treg cells. Given the dominant role of Treg cells in tumor immune evasion mechanisms, 4-1BB signaling represents an attractive target for favorably tipping the Teff:Treg balance toward Teff cells with important implications for cancer immunotherapy.

  17. Analysis of changes in the percentage of B (CD19) and T (CD3) lymphocytes, nk cells, subsets CD4, CD8 in differentiated thyroid cancer patients treated with iodine-131

    International Nuclear Information System (INIS)

    Objective: To evaluate the changes in the percentage of B (CD19) and T (CD3) lymphocytes, NK cells, subsets CD4, CD8 in patients with differentiated thyroid carcinoma (DTC) who received iodine-131 for therapeutic purposes. Methods: In this study, 102 DTC patients were divided into three groups. Group A, 8 cases received 1850 MBq of iodine-131 for the remnant thyroid ablation. Group B, 43 cases received 3700 MBq of iodine-131 for the treatment of cervical lymph node metastasis. Group C, 51 cases received 7400 MBq of iodine-131 for remote metastasis. All patients were in a hypothyroid state at the time of administration of iodine-131 and resumed L-thyroxine (2μg/Kg/day) 5 days after iodine-131 administration. The percentage of B and T lymphocytes, NK cells, subsets CD4, CD8 in peripheral blood were serially analyzed at baseline and at days 7, 30 and 90 after iodine-131 administration using a Coulter EPICS XL cytometer. Ten healthy individuals were used as a control group for lymphocyte subset values. Results: Comparing the basal lymphocyte subset levels in groups A, B and C with the control group, only NK cells showed significantly higher levels in patients than in controls (P=0.043). In group A, only the percentage of NK cells (P=0.031) and B cells (P =0.024) were reduced at day 7. In group B, a decrease in the percentage of NK cells at days 7(P=0.005), 30 (P=0.021) was observed, while a significant decrease in the percentage of B cells was only observed at day 7(P=0.006). Among T cells, only CD4+ was obviously affected, resulting in a reduction in the CD4+/CD8+ ratio at day 30 (P=0.034). In group C, patients showed a decrease in the percentage of NK cells at days 7 (P=0.023), 30 (P=0.006). A decrease in the percentage of both B and T lymphocytes was observed at days 7(P=0.020, 0.018 respectively), 30(P=0.041, 0.025 respectively). Among T cells, a decrease in the percentage of CD4+ and an increase in the percentage of CD8+ were observed, resulting in a marked

  18. Where CD4 + CD25 + T reg cells impinge on autoimmune diabetes

    OpenAIRE

    Chen, Zhibin; Herman, Ann E.; Matos, Michael; Mathis, Diane; Benoist, Christophe

    2005-01-01

    Foxp3 is required for the generation and activity of CD4 + CD25 + regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in ...

  19. Transcriptional characteristics of CD4+ T cells in young asthmatic children: RORC and FOXP3 axis

    Directory of Open Access Journals (Sweden)

    Hamzaoui A

    2011-11-01

    Full Text Available Agnes Hamzaoui1,2,*, Haïfa Maalmi1,*, Anissa Berraïes1,2, Hanadi Abid1,2, Jamel Ammar1,2, Kamel Hamzaoui11Department of Pediatrics and Respiratory Disease, Homeostasis and Cell Dysfunction Unit Research, Abderrahman Mami Hospital, Ariana, Tunisia; 2Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia *These authors contributed to this work equallyBackground: Asthma is a chronic inflammatory disorder, hypothetically caused by autoreactive Th2 cells, whereas Th1 and regulatory T cells may confer protection. The development of Th subpopulations is dependent on the expression of lineage-specific transcription factors.Purpose: This study aimed to assess the balance of CD4+ T cell populations in asthmatic children.Methods: Peripheral blood mononuclear cells (PBMC mRNA expression was assessed in 30 asthmatic children (18 patients with mild asthma and 12 with moderate asthma. Real-time polymerase chain reaction (RT-PCR quantified TBX21, GATA-3, RORC, FOXP3, and EBI3 mRNA expression. Intracellular cytokine expression of IL-2, IL-4, IL-10, and IFN-γ in CD4+ T cells in asthmatic children was measured by flow cytometry. IL-6 and IL-17 cytokines were assessed in serum by enzyme-linked immunosorbent assay (ELISA.Results: A significant increase was found in the percentage of CD4+ and CD8+ T cell-producing IL-4, IL-6, and IL-17. A decreased percentage of CD4+ producing IFN-γ in asthmatic children was found. Expression of GATA-3 (Th2, retinoid-related orphan receptor C (RORC (Th17, and EBI3 were increased in asthmatic patients compared to healthy controls. Expression of FOXP3 (Treg and TBX21 (Th1 were decreased (P < 0.0001 and P < 0.0001 in asthmatic children. Analysis of transcription factor ratios revealed an increase in the RORC/FOXP3 (P = 0.0001, and a significant decrease of TBX21/GATA-3 (P = 0.0001 ratios in patients with asthma.Conclusion: Young asthmatics were characterized by increased IL-4 production and low IFN-γ synthesis. The

  20. 56 Increased Frequency of CD4+ CD25+ FOXP3- in Allergic Conjunctivitis Patients

    OpenAIRE

    Galicia-Carreón, Jorge; Alonso-Sánchez, Miguel E.; Robles-Contreras, Atzin; Hong, Enrique; Chávez, Raul; Jiménez-Martínez, Maria C.

    2012-01-01

    Background Allergic conjunctivitis (AC) is one of the most common eye disorders in clinical practice. It has been shown that AC is a disorder mediated by Th2 lymphocytes producing IL-4 and IL-5, where the eye damage is caused by a type I hypersensitivity. It has been suggested in asthma and rhinitis that T regulatory cells (Tregs) CD4+ CD25+ FOXP3+ have been involved in control allergic status, favoring an optimal microenvironment with immunosuppressive cytokines (IL-10, TGF-β). However is un...

  1. CD4+CD45RBHi Interleukin-4 Defective T Cells Elicit Antral Gastritis and Duodenitis

    OpenAIRE

    Dohi, Taeko; Fujihashi, Kohtaro; Koga, Toshiya; Etani, Yuri; Yoshino, Naoto; Kawamura, Yuki I.; Mcghee, Jerry R

    2004-01-01

    We have analyzed the gastrointestinal inflammation which develops following adoptive transfer of IL-4 gene knockout (IL-4−/−) CD4+CD45RBHi (RBHi) T cells to severe combined immunodeficient (SCID) or to T cell-deficient, T cell receptor β and δ double knockout (TCR−/−) mice. Transfer of IL-4−/− RBHi T cells induced a similar type of colitis to that seen in SCID or TCR−/− recipients of wild-type (wt) RBHi T cells as reported previously. Interestingly, transfer of both wt and IL-4−/− RBHi T cell...

  2. Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition.

    Science.gov (United States)

    Melillo, Bruno; Liang, Shuaiyi; Park, Jongwoo; Schön, Arne; Courter, Joel R; LaLonde, Judith M; Wendler, Daniel J; Princiotto, Amy M; Seaman, Michael S; Freire, Ernesto; Sodroski, Joseph; Madani, Navid; Hendrickson, Wayne A; Smith, Amos B

    2016-03-10

    The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4-7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies. PMID:26985324

  3. Isolated CD39 Expression on CD4+ T Cells Denotes both Regulatory and Memory Populations

    OpenAIRE

    Zhou, Q.; Yan, J.; Putheti, P.; Wu, Y.; X. Sun; Toxavidis, V.; Tigges, J.; Kassam, N.; Enjyoji, K.; Robson, S C; Strom, T. B.; Gao, W.

    2009-01-01

    Foxp3+ regulatory T cells (Tregs) express both ectoenzymes CD39 and CD73, which in tandem hydrolyze pericellular ATP into adenosine, an immunoinhibitory molecule that contributes to Treg suppressive function. Using Foxp3GFP knockin mice, we noted that the mouse CD4+CD39+ T-cell pool contains two roughly equal size Foxp3+ and Foxp3− populations. While Foxp3+CD39+ cells are CD73bright and are the bone fide Tregs, Foxp3−CD39+ cells do not have suppressive activity and are CD44+CD62L−CD25−CD73dim...

  4. Dichotomy in the human CD4+ T-cell response to Leishmania parasites

    DEFF Research Database (Denmark)

    Kemp, M; Kurtzhals, J A; Kharazmi, A;

    1994-01-01

    Leishmania parasites cause human diseases ranging from self-healing cutaneous ulcers to fatal systemic infections. In addition, many individuals become infected without developing disease. In mice the two subsets of CD4+ T cells, Th1 and Th2, have different effects on the outcome of experimental...... Leishmania infections. Th1 cells producing interferon-gamma (IFN-gamma) mediate resistance, whereas Th2 cells producing interleukin-4 (IL-4) and IL-10 are associated with susceptibility and exacerbation. Evidence is accumulating that a Th1/Th2 dichotomy in the T-cell response to Leishmania exists also...

  5. Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells

    OpenAIRE

    Meininger, Isabel; Griesbach, Richard A.; Hu, Desheng; Gehring, Torben; Seeholzer, Thomas; Bertossi, Arianna; Kranich, Jan; Oeckinghaus, Andrea; Eitelhuber, Andrea C; Greczmiel, Ute; Gewies, Andreas; Schmidt-Supprian, Marc; Ruland, Jürgen; Brocker, Thomas; Heissmeyer, Vigo

    2016-01-01

    MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4+ T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify...

  6. Chemokines involved in protection from colitis by CD4+CD25+ regulatory T cells

    DEFF Research Database (Denmark)

    Kristensen, Nanna Ny; Brudzewsky, Dan; Gad, Monika;

    2006-01-01

    /chemokine receptor-specific gene expression profiling system of 67 genes, the authors have determined the expression profile of chemokine and chemokine receptor genes in the rectum of colitic mice and in mice that have been protected fromcolitis by CD4CD25 regulatory T cells. In mice protected from colitis, the...... authors found down regulation of the mRNA expression of the inflammatory chemokine receptors CCR1 and CXCR3 and their ligands CXCL9, CXCL10, CCL5, and CCL7. Also the transcripts for CCR9, CCL25, CCL17, and CXCL1 are found down regulated in protected compared with colitic animals. In addition, the authors...

  7. Maturation of Dendritic Cells & HIV Transmission to CD4(+) T cells

    OpenAIRE

    Izquierdo-Useros, Nuria

    2009-01-01

    Las células dendríticas (DCs) están especializadas en la presentación de antígeno. Sin embargo, las DCs expuestas al virus de la inmunodeficiencia humana (VIH) también son capaces de transmitir una potente infección citopática a los linfocitos T CD4+, un proceso que frecuentemente se ha relacionado con la capacidad que tiene el receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) para unirse de forma específica a la glicoproteína de la envuelta vi...

  8. Maturation of dendritic cells & HIV-1 transmission to CD4+ T cells

    OpenAIRE

    Izquierdo Useros, Nuria

    2009-01-01

    Descripció del recurs: 22 febrer de 2010 Las células dendríticas (DCs) están especializadas en la presentación de antígeno. Sin embargo, las DCs expuestas al virus de la inmunodeficiencia humana (VIH) también son capaces de transmitir una potente infección citopática a los linfocitos T CD4+, un proceso que frecuentemente se ha relacionado con la capacidad que tiene el receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) para unirse de forma esp...

  9. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism.

    Science.gov (United States)

    Oida, Takatoku; Zhang, Xingmin; Goto, Masao; Hachimura, Satoshi; Totsuka, Mamoru; Kaminogawa, Shuichi; Weiner, Howard L

    2003-03-01

    Murine CD4(+)CD25(+) regulatory cells have been reported to express latency-associated peptide (LAP) and TGF-beta on the surface after activation, and exert regulatory function by the membrane-bound TGF-beta in vitro. We have now found that a small population of CD4(+) T cells, both CD25(+) and CD25(-), can be stained with a goat anti-LAP polyclonal Ab without being stimulated. Virtually all these LAP(+) cells are also positive for thrombospondin, which has the ability to convert latent TGF-beta to the active form. In the CD4(+)CD45RB(high)-induced colitis model of SCID mice, regulatory activity was exhibited not only by CD25(+)LAP(+) and CD25(+)LAP(-) cells, but also by CD25(-)LAP(+) cells. CD4(+)CD25(-)LAP(+) T cells were part of the CD45RB(low) cell fraction. CD4(+)CD25(-)LAP(-)CD45RB(low) cells had minimal, if any, regulatory activity in the colitis model. The regulatory function of CD25(-)LAP(+) cells was abrogated in vivo by anti-TGF-beta mAb. These results identify a new TGF-beta-dependent regulatory CD4(+) T cell phenotype that is CD25(-) and LAP(+). PMID:12594277

  10. Isolation and partial characterization of peripheral blood CD4+ T cell clones expressing γδT cell receptors

    International Nuclear Information System (INIS)

    Rare T cell clones bearing both CD4 and T cell receptors (TCRγ and TCRδ) were obtained from human peripheral blood by cell sorting using anti-CD4 and anti-TCRδ1 antibodies. All the clones established were reactive with anti-TCRγδ1 antibody, whereas only about 20 % of the clones showed reactivity with anti-δTCS1 antibody. Unlike CD4+ T cells bearing TCRαβ, all the clones tested were lectin-dependent and showed CD3 antibody-redirected cytolytic activity. About 60 % exhibited natural killer cell-like activity. Immunoprecipitation analysis of TCRγδ showed that each clone expressed either a disulfide-linked or nondisulfide-linked heterodimer consisting of 37-44 kilodalton TCRγ and TCRδ chains. Southern blot analyses of TCRγ and TCRδ genes revealed some identical rearrangement patterns, suggesting the limited heterogeneity of CD4+TCRγδ+ T cells in peripheral blood. (author)

  11. Thalidomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood.

    Science.gov (United States)

    Shannon, E J; Ejigu, M; Haile-Mariam, H S; Berhan, T Y; Tasesse, G

    1992-03-01

    Thalidomide is well documented as being an effective drug in the treatment of erythema nodosum leprosum (ENL). The mechanism of action of thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully determined. Lepromatous leprosy patients experiencing ENL have been reported to have an increase in the ratio of CD4+ to CD8+ cells in their blood and ENL skin lesions. Thalidomide has been shown to cause a decrease in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males. This decrease was due to a significant reduction in the numbers of Cd4+ lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In this study, thalidomide's effectiveness in halting chronic ENL and arresting a relapse into ENL was consistently associated with a decrease in the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy patients. PMID:1569817

  12. Proliferation and apoptosis of lamina propria CD4+ T cells from scid mice with inflammatory bowel disease

    DEFF Research Database (Denmark)

    Bregenholt, S; Reimann, J; Claesson, Mogens Helweg

    1998-01-01

    Scid mice transplanted with low numbers of syngeneic CD4+ T cells, develop a chronic and lethal inflammatory bowel disease (IBD) within 4-6 months. We have used in vivo 5-bromo2-deoxy-uridine (BrdU) labeling to assess the proliferation of lamina propria-derived CD4+ T cells in diseased scid mice....... The hourly rate of renewal of colonic lamina propria CD4+ T cells in diseased mice was 7% compared with 1.5% in normal BALB/c control mice. Transplantation of scid mice with in vitro activated CD4+ T cells accelerated the disease onset and development in a cell dose-dependent fashion when compared...

  13. Interdisciplinary Evaluation of Broadly-Reactive HLA Class II Restricted Epitopes Eliciting HIV-Specific CD4+T Cell Responses

    DEFF Research Database (Denmark)

    Buggert, M.; Norström, M.; Lundegaard, Claus; Lund, Ole; Nielsen, Morten; Karlsson, A. C.

    2011-01-01

    Background: CD4+ T cells orchestrate immune protection by ‘‘helping’’ other cells of our immune system to clear viral infections. It is well known that the preferential infection and depletion of CD4+ T cells contributes to hampered systemic T cell help following HIV infection. However, the...... functional and immunodominant discrepancies of CD4+ T cell responses targeting promiscuous MHC II restricted HIV epitopes remains poorly defined. Thus, utilization of interdisciplinary approaches might aid revealing broadly- reactive peptides eliciting CD4 + T cell responses. Methods: We utilized the novel...... bioinformatic prediction program NetMHCIIpan to select 64 optimized MHC II restricted epitopes located in the HIV Gag, Pol, Env, Nef and Tat regions. The epitopes were selected to cover the global diversity of the virus (multiple subtypes) and the human immune system(diverse MHC II types). Optimized...

  14. Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(-/-) mice

    DEFF Research Database (Denmark)

    Riberdy, J M; Christensen, Jan Pravsgaard; Branum, K; Doherty, P C

    2000-01-01

    Optimal expansion of influenza virus nucleoprotein (D(b)NP(366))-specific CD8(+) T cells following respiratory challenge of naive Ig(-/-) microMT mice was found to require CD4(+) T-cell help, and this effect was also observed in primed animals. Absence of the CD4(+) population was consistently...... correlated with diminished recruitment of virus-specific CD8(+) T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8(+) set generated during the recall response in Ig(-/-) mice primed at least 6 months previously showed a normal profile of gamma interferon...... production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4(+) T-cell response. Both the magnitude and the localization profiles of virus-specific CD8(+) T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4(+) T...

  15. Internalization, lysosomal degradation and new synthesis of surface membrane CD4 in phorbol ester-activated T-lymphocytes and U-937 cells

    DEFF Research Database (Denmark)

    Petersen, C M; Christensen, E I; Andresen, B S;

    1992-01-01

    degradation was low in resting cells. Endocytosis and/or degradation of anti-CD4 mAb was suppressed by H7, and by inhibitors of membrane traffic (Monensin) and lysosome function (methylamine, chloroquine). Immunocytochemistry localized CD4 to the surface of unstimulated T-cells. Upon PMA stimulation...... occasional labeling was seen in endosomes but whole cell CD4 decreased dramatically. However, methylamine-treated PMA blasts showed accumulation of CD4 in lysosomes and accordingly, pulse-chase experiments in biolabeled cell cultures suggested a manifest reduction of CD4 half-life in response to PMA. Despite...... lysosomal degradation of membrane CD4. Transport of CD4 to the cell surface and CD4 synthesis is unaffected by activation....

  16. Evaluation of PIMATM CD4 System for Decentralization of Immunological Monitoring of HIV-Infected Patients in Senegal

    Science.gov (United States)

    Faye, Babacar; Mbow, Moustapha; Camara, Makhtar; Cissé, Cathy; Diouf, Salimata Guèye; Ndao, Babacar; Djibo, Audrey; Sylla Niang, Maguette Dème; Ndiaye, Tandakha; Grillo, Michael P.; Dièye, Alioune

    2016-01-01

    Background HIV infection is a concern in the army troupes because of the risk behaviour of the military population. In order to allow regular access to CD4+ T cell enumeration of military personnel as well as their dependents and civilians living with HIV, the Senegalese Army AIDS program is implementing PIMATM Alere technology in urban and semi-urban military medical centres. Validation such device is therefore required prior their wide implementation. The purpose of this study was to compare CD4+ T cell count measurements between the PIMATM Alere to the BD FACSCountTM. Methodology We selected a total of 200 subjects including 50 patients with CD4+ T-cells below 200/mm3, 50 between 200 and 350/mm3, 50 between 351 and 500/mm3, and 50 above 500/mm3. CD4+ T-cell count was performed on venous blood using the BD FASCountTM as reference method and the PIMATM Point of Care technology. The mean biases and limits of agreement between the PIMATM Alere and BD FACSCountTM were assessed with the Bland-Altman analysis, the linear regression performed using the Passing-Bablok regression analysis, and the percent similarity calculated using the Scott method. Results Our data have shown a mean difference of 22.3 cells/mm3 [95%CI:9.1–35.5] between the BD FACSCountTM and PIMATM Alere CD4 measurements. However, the mean differences of the two methods was not significantly different to zero when CD4+ T-cell count was below 350/mm3 (P = 0.76). The Passing-Bablok regression in categorized CD4 counts has also showed concordance correlation coefficient of 0.89 for CD4+ T cell counts below 350/mm3 whilst it was 0.5 when CD4 was above 350/mm3. Conclusion Overall, our data have shown that for low CD4 counts, the results from the PIMATM Alere provided accurate CD4+ T cell counts with a good agreement compared to the FACSCountTM. PMID:27166955

  17. Evaluation of PIMATM CD4 System for Decentralization of Immunological Monitoring of HIV-Infected Patients in Senegal.

    Directory of Open Access Journals (Sweden)

    Babacar Faye

    Full Text Available HIV infection is a concern in the army troupes because of the risk behaviour of the military population. In order to allow regular access to CD4+ T cell enumeration of military personnel as well as their dependents and civilians living with HIV, the Senegalese Army AIDS program is implementing PIMATM Alere technology in urban and semi-urban military medical centres. Validation such device is therefore required prior their wide implementation. The purpose of this study was to compare CD4+ T cell count measurements between the PIMATM Alere to the BD FACSCountTM.We selected a total of 200 subjects including 50 patients with CD4+ T-cells below 200/mm3, 50 between 200 and 350/mm3, 50 between 351 and 500/mm3, and 50 above 500/mm3. CD4+ T-cell count was performed on venous blood using the BD FASCountTM as reference method and the PIMATM Point of Care technology. The mean biases and limits of agreement between the PIMATM Alere and BD FACSCountTM were assessed with the Bland-Altman analysis, the linear regression performed using the Passing-Bablok regression analysis, and the percent similarity calculated using the Scott method.Our data have shown a mean difference of 22.3 cells/mm3 [95%CI:9.1-35.5] between the BD FACSCountTM and PIMATM Alere CD4 measurements. However, the mean differences of the two methods was not significantly different to zero when CD4+ T-cell count was below 350/mm3 (P = 0.76. The Passing-Bablok regression in categorized CD4 counts has also showed concordance correlation coefficient of 0.89 for CD4+ T cell counts below 350/mm3 whilst it was 0.5 when CD4 was above 350/mm3.Overall, our data have shown that for low CD4 counts, the results from the PIMATM Alere provided accurate CD4+ T cell counts with a good agreement compared to the FACSCountTM.

  18. Changes in Th1 cells and CD4+CD25+Treg cells in non-obese diabetic mice at early stage of diabetes

    Directory of Open Access Journals (Sweden)

    Hong-jun WANG

    2013-11-01

    Full Text Available Objective To investigate the changes in Th1 cells and CD4+CD25+Treg cells in non-obese diabetic (NOD mice at early stage of diabetes, and to evaluate the significance of these changes. Methods Four week- (group A, 8 week- (group B and 16 week-old (group C female NOD mice (8 each were used in present study. The spleen, thymus and pancreas were harvested. Th1 and CD4+CD25+Treg cells in spleen were determined by flow cytometer, and the ratios of Th1/CD4+T, CD4+CD25+Treg/CD4+T and Th1/CD4+CD25+Treg were calculated. Subsequently, CD4–CD8–T, CD4+CD8+T, CD4–CD8+T and CD4+CD8–T cells in thymus were determined by flow cytometer, and the ratio of CD25+Treg/CD4+CD8–T was calculated. The histopathological changes in pancreas were also evaluated by HE staining and immunohistochemistry staining. Results The proportion of Th1 cells in spleen and the ratios of Th1/CD4+T and Th1/CD4+CD25+Treg were higher significantly in group C than in group A and B. However, no significant differences were found in the proportion of spleen CD4+CD25+Treg cells and the ratio of CD4+CD25+Treg/CD4+T among the three groups. Compared with group A, no obvious changes were found in thymus CD4–CD8–T, CD4+CD8+T, CD4–CD8+T and CD4+CD8–T cells in group B and C, but the ratio of thymus CD25+Treg/CD4+CD8–T increased significantly in group B and C. Lymphocytic infiltration was observed in pancreatic islets of group B and C as shown with HE staining, but Foxp3+T cells were not seen in pancreatic islets by immunohistochemistry. Conclusion Th1 cells are gradually increased at early stage of diabetes in NOD mice, but CD4+CD25+Treg cells are relatively default. These changes may play an important role in the progress of diabetes. DOI: 10.11855/j.issn.0577-7402.2013.11.004

  19. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma

    OpenAIRE

    Cabrera, Roniel; Ararat, Miguel; Xu, Yiling; Brusko, Todd; Wasserfall, Clive; Atkinson, Mark A.; Chang, Lung Ji; Liu, Chen; Nelson, David R.

    2012-01-01

    Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25− effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from periphe...

  20. Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study.

    Directory of Open Access Journals (Sweden)

    Zheng-Feng Zhu

    Full Text Available OBJECTIVE: CD4(+ latency-associated peptide (LAP(+ regulatory T cells (Tregs are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS has not been explored. We designed to investigate whether circulating frequency and function of CD4(+LAP(+ Tregs are defective in ACS. METHODS: One hundred eleven ACS patients (acute myocardial infarction and unstable angina and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA and chest pain syndrome (CPS. The frequencies of circulating CD4(+LAP(+ Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP on CD4(+ T cells were determined by flow cytometry. The function of CD4(+LAP(+ Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10 and transforming growth factor-β protein (TGF-β levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs was measured by real time-polymerase chain reaction. RESULTS: We found ACS patients had a significantly lower frequency of circulating CD4(+LAP(+ Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+ T cells and the serum levels of TGF-β in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. CONCLUSIONS: A novel regulatory T cell subset, defined as CD4(+LAP(+ T cells is defective in ACS patients.

  1. HIV/AIDS患者CD4细胞水平与TB的发病情况分析

    Institute of Scientific and Technical Information of China (English)

    周平

    2010-01-01

    目的 分析柳州市HIV/AIDS患者合并TB发病情况,探讨HIV/AIDS患者的CD4细胞水平与TB的发病关系.方法 对180例HIV/AIDS患者的CD4细胞水平与TB的发病情况进行回顾性分析.结果 ①180例HIV/AIDS患者中,合并TB34例,TB发病率为18.9%.②CD4细胞越低,TB发病率越高:180例HIV/AIDS病人中,CD4细胞≤50/mm3组TB患者8例,TB发病率为25%;CD4细胞51-200/mm3组TB患者14例,TB发病率为23%;CD4细胞201-350/mm3组TB患者7例,TB发病率为15.9%;CD4>350个/mm3组TB患者5例,TB发病率为11.6%.结论 HIV/AIDS患者的CD4细胞水平与TB的发病有密切关系,应加强对HIV/AIDS患者的结核病检查工作,以便及早发现和治疗结核病.

  2. CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller

    Directory of Open Access Journals (Sweden)

    Burwitz Benjamin J

    2012-11-01

    Full Text Available Abstract Background Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. Results Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. Conclusions Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.

  3. Selective Loss of Early Differentiated, Highly Functional PD1high CD4 T Cells with HIV Progression.

    Science.gov (United States)

    Paris, Robert M; Petrovas, Constantinos; Ferrando-Martinez, Sara; Moysi, Eirini; Boswell, Kristin L; Archer, Eva; Yamamoto, Takuya; Ambrozak, David; Casazza, Joseph P; Haubrich, Richard; Connors, Mark; Ake, Julie; Kim, Jerome H; Koup, Richard A

    2015-01-01

    The role of PD-1 expression on CD4 T cells during HIV infection is not well understood. Here, we describe the differential expression of PD-1 in CD127high CD4 T cells within the early/intermediate differentiated (EI) (CD27highCD45RAlow) T cell population among uninfected and HIV-infected subjects, with higher expression associated with decreased viral replication (HIV-1 viral load). A significant loss of circulating PD-1highCTLA-4low CD4 T cells was found specifically in the CD127highCD27highCD45RAlow compartment, while initiation of antiretroviral treatment, particularly in subjects with advanced disease, reversed these dynamics. Increased HIV-1 Gag DNA was also found in PD-1high compared to PD-1low ED CD4 T cells. In line with an increased susceptibility to HIV infection, PD-1 expression in this CD4 T cell subset was associated with increased activation and expression of the HIV co-receptor, CCR5. Rather than exhaustion, this population produced more IFN-g, MIP1-a, IL-4, IL-10, and IL-17a compared to PD-1low EI CD4 T cells. In line with our previous findings, PD-1high EI CD4 T cells were also characterized by a high expression of CCR7, CXCR5 and CCR6, a phenotype associated with increased in vitro B cell help. Our data show that expression of PD-1 on early-differentiated CD4 T cells may represent a population that is highly functional, more susceptible to HIV infection and selectively lost in chronic HIV infection. PMID:26678998

  4. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite.

    Science.gov (United States)

    Combe, Crescent L; Moretto, Magali M; Schwartzman, Joseph D; Gigley, Jason P; Bzik, David J; Khan, Imtiaz A

    2006-04-25

    IFN-gamma-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-gamma-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15-/- mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Down-regulated CD4+ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4+ T cells from IL-15-/- mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4+ T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4+ T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4+ T cell-mediated autoimmune diseases. PMID:16614074

  5. Prevention of Immunodeficiency Virus induced CD4+ T-Cell depletion by prior infection with a non-pathogenic virus

    OpenAIRE

    Terwee, Julie A.; Carlson, Jennifer K.; Sprague, Wendy S.; Sondgeroth, Kerry S.; Shropshire, Sarah B.; Troyer, Jennifer L.; VandeWoude, Sue

    2008-01-01

    Immune dysregulation initiated by a profound loss of CD4+ T-cells is fundamental to HIV-induced pathogenesis. Infection of domestic cats with a non-pathogenic lentivirus prevalent in the puma (puma lentivirus, PLV or FIVPCO) prevented peripheral blood CD4+ T-cell depletion caused by subsequent virulent FIV infection. Maintenance of this critical population was not associated with a significant decrease in FIV viremia, lending support to the hypothesis that direct viral cytopathic effect is no...

  6. Independent clinical significance of HIV antigen determination and CD4 counts in anti-HIV positive patients

    DEFF Research Database (Denmark)

    Skinhøj, P; Hofmann, B; Jacobsen, K D;

    1989-01-01

    identified a separate subpopulation. For 138 asymptomatic patients followed prospectively both laboratory parameters predicted HIV-related events, the relative risk factor being 4 for low CD4 value and 6 for presence of HIV antigen. Individuals presenting with HIV antigen and decreased CD4 count all...... developed disease within 18 months, the relative risk factor being 24. Thus the 2 markers, when measured together, effectively separated asymptomatic HIV-infected patients into 1 of 3 risk categories....

  7. A microfluidic device for practical label-free CD4+ T cell counting of HIV-infected subjects

    OpenAIRE

    Cheng, Xuanhong; Irimia, Daniel; Dixon, Meredith; Sekine, Kazuhiko; Demirci, Utkan; Zamir, Lee; Tompkins, Ronald G.; Rodriguez, William; Toner, Mehmet

    2006-01-01

    Practical HIV diagnostics are urgently needed in resource-limited settings. While HIV infection can be diagnosed using simple, rapid, lateral flow immunoassays, HIV disease staging and treatment monitoring require accurate counting of a particular white blood cell subset, the CD4+ T lymphocyte. To address the limitations of current expensive, technically demanding and/or time-consuming approaches, we have developed a simple CD4 counting microfluidic device. This device uses cell affinity chro...

  8. A New Humanized HLA Transgenic Mouse Model of Multiple Sclerosis Expressing Class II on Mouse CD4 T Cells

    OpenAIRE

    Mangalam, Ashutosh; Rodriguez, Moses; David, Chella

    2007-01-01

    Among all the genetic factors associated with MS susceptibility, strongest association has been seen with expression of certain MHC class II molecules, although analysis of their exact function remains complicated. In general expression of class II is restricted to professional antigen presenting cells, however human but not mice CD4+ T cells express class II on their surface. Functional studies of classII+CD4+ T cells have been hampered due to lack of proper animal model. Here we describe de...

  9. Kinetic and structural analysis of mutant CD4 receptors that are defective in HIV gp120 binding

    OpenAIRE

    Wu, Hao; Myszka, David G.; Tendian, Susan W.; Brouillette, Christie G.; Sweet, Ray W.; Chaiken, Irwin M.; Hendrickson, Wayne A.

    1996-01-01

    The T-cell antigen coreceptor CD4 also serves as the receptor for the envelope glycoprotein gp120 of HIV. Extensive mutational analysis of CD4 has implicated residues from a portion of the extracellular amino-terminal domain (D1) in gp120 binding. However, none of these proteins has been fully characterized biophysically, and thus the precise effects on molecular structure and binding interactions are unknown. In the present study, we produced soluble versions of three...

  10. Selective Loss of Early Differentiated, Highly Functional PD1high CD4 T Cells with HIV Progression.

    Directory of Open Access Journals (Sweden)

    Robert M Paris

    Full Text Available The role of PD-1 expression on CD4 T cells during HIV infection is not well understood. Here, we describe the differential expression of PD-1 in CD127high CD4 T cells within the early/intermediate differentiated (EI (CD27highCD45RAlow T cell population among uninfected and HIV-infected subjects, with higher expression associated with decreased viral replication (HIV-1 viral load. A significant loss of circulating PD-1highCTLA-4low CD4 T cells was found specifically in the CD127highCD27highCD45RAlow compartment, while initiation of antiretroviral treatment, particularly in subjects with advanced disease, reversed these dynamics. Increased HIV-1 Gag DNA was also found in PD-1high compared to PD-1low ED CD4 T cells. In line with an increased susceptibility to HIV infection, PD-1 expression in this CD4 T cell subset was associated with increased activation and expression of the HIV co-receptor, CCR5. Rather than exhaustion, this population produced more IFN-g, MIP1-a, IL-4, IL-10, and IL-17a compared to PD-1low EI CD4 T cells. In line with our previous findings, PD-1high EI CD4 T cells were also characterized by a high expression of CCR7, CXCR5 and CCR6, a phenotype associated with increased in vitro B cell help. Our data show that expression of PD-1 on early-differentiated CD4 T cells may represent a population that is highly functional, more susceptible to HIV infection and selectively lost in chronic HIV infection.

  11. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis

    OpenAIRE

    Huber, Magdalena; Lohoff, Michael

    2015-01-01

    Summary The activation of naive CD4+ and CD8+ T cells in response to antigen and their subsequent proliferation and differentiation into effectors are important features of a cell-mediated immune response. CD4+ T cells (also known as T helper cells, Th) differentiate into several subpopulations including Th1, Th2, Th9, Th17, Tfh and Treg cells, characterized by specific cytokine profiles and effector functions. However, recent evidence indicates that CD8+ T cells (termed cytotoxic T lymphocyt...

  12. CD4+CD25−Foxp3+ T cells play a role in tuberculous hydrothorax rather than malignant hydrothorax

    OpenAIRE

    Tang, Ying; Peng, Li-Ping; Qin, Gui-Xiang; Sun, Jing-Ting; Xu, Li-Jun; Jiang, Yan-Fang

    2015-01-01

    Background Foxp3+ T cells regulate inflammation and tumorigenesis. However, little is known about the role of different subsets of Foxp3+ T cells in malignant or tuberculous hydrothorax. Methods The numbers of CD4+CD25+Foxp3+, CD4+CD25−Foxp3+ T cells and the levels of some inflammatory cytokines in patients with tuberculous hydrothorax, malignant hydrothorax, and healthy controls (HCs) were examined by flow cytometry and ELISA. The potential association between the numbers of different subset...

  13. The Transmembrane E3 Ligase GRAIL Ubiquitinates and Degrades CD83 on CD4 T Cells1

    OpenAIRE

    Su, Leon L.; Iwai, Hideyuki; Lin, Jack T; Fathman, C. Garrison

    2009-01-01

    Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes, including T cell activation and tolerance. We have previously demonstrated that GRAIL (gene related to anergy in lymphocytes), a transmembrane RING finger ubiquitin E3 ligase, initially described as induced during the induction of CD4 T cell anergy, is also expressed in resting CD4 T cells. In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marke...

  14. Quantitative analysis of the acute and long-term CD4(+) T-cell response to a persistent gammaherpesvirus

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Doherty, P C

    1999-01-01

    compensatory response. The peak frequency within the splenic CD4(+) T-cell population may reach 1:50 in the acute response; it then drops to 1:400 to 1:500 within 4 months and stays at that level in the very long term. Sorting for L-selectin (CD62L) expression established that all virus-specific CD4(+) T cells...

  15. Association of Hepatitis C Virus Infection With CD4/CD8 Ratio in HIV-Positive Women

    Science.gov (United States)

    O'Brien, Thomas R.; Prokunina-Olsson, Ludmila; Augenbraun, Michael; Plankey, Michael; Karim, Roksana; Sarkar, Monika; French, Audrey L.; Pierce, Chris; Strickler, Howard D.; Anastos, Kathryn

    2016-01-01

    Background: Recent studies reported that the CD4/CD8 T-cell ratio is inversely associated with biomarkers traditionally used to measure immune activation and systemic inflammation in highly active antiretroviral therapy–treated HIV-infected (HIV+) patients. The relation of hepatitis C virus (HCV) coinfection with the CD4/CD8 ratio in HIV+ patients is unknown. Methods: We examined 50,201 CD4/CD8 ratios measured over 20 years in 3 groups of HIV+ women enrolled in the Women's Interagency HIV Study: HCV antibody negative (n = 1734), cleared HCV (n = 231), and chronic HCV (n = 751) in multivariate models. IFNL4-ΔG genotype and HCV viral load were also considered. Results: Compared with HCV antibody negative status, chronic HCV infection was associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification (β = −0.08; P = 0.002). Cleared HCV (β = −0.10; P = 0.0009), but not IFNL4-ΔG genotype or HCV viral load, was also associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification. Conclusions: The association of HCV coinfection with CD4/CD8 ratio is consistent with previously observed associations of HCV coinfection with biomarkers traditionally used to measure immune activation and systemic inflammation in HIV+ patients. These data provide additional support for the use of CD4/CD8 ratio for routine monitoring of immune activation and inflammation in HIV+ patients, including those with HIV/HCV coinfection; however, the unexpected association between cleared HCV and lower CD4/CD8 ratio requires additional study. PMID:27183178

  16. POC CD4 Testing Improves Linkage to HIV Care and Timeliness of ART Initiation in a Public Health Approach: A Systematic Review and Meta-Analysis

    OpenAIRE

    Vojnov, Lara; Markby, Jessica; Boeke, Caroline; Harris, Lindsay; Ford, Nathan; Peter, Trevor

    2016-01-01

    Background CD4 cell count is an important test in HIV programs for baseline risk assessment, monitoring of ART where viral load is not available, and, in many settings, antiretroviral therapy (ART) initiation decisions. However, access to CD4 testing is limited, in part due to the centralized conventional laboratory network. Point of care (POC) CD4 testing has the potential to address some of the challenges of centralized CD4 testing and delays in delivery of timely testing and ART initiation...

  17. Early recovery of CD4 T lymphocytes in children on highly active antiretroviral therapy. Dutch study group for children with HIV infections

    OpenAIRE

    Cohen Stuart, J. W.; Slieker, W.A.; Rijkers, G T; Noest, A. J.; Boucher, C. A. B.; Suur, M.H.; De Boer, R. J.; Geelen, S.P.; Scherpbier, H.J.; Hartwig, N G; Hooijkaas, H; Roos, M T; Graeff-Meeder, B. de; de Groot, R.

    1998-01-01

    Regeneration of CD4+ T lymphocytes has been shown to be thymus-dependent in bone marrow transplant recipients and after intensive chemotherapy. The rate of CD4+ T cell regeneration is correlated positively with enlargement of the thymus, as shown on radiographs, and higher rates of CD4+ T lymphocyte regeneration were observed in children as compared with adults, consistent with thymic function diminishing with age. We hypothesized that in HIV infected patients CD4+ T cell recovery during high...

  18. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

    Science.gov (United States)

    Martins, Karen A.O.; Cooper, Christopher L.; Stronsky, Sabrina M.; Norris, Sarah L.W.; Kwilas, Steven A.; Steffens, Jesse T.; Benko, Jacqueline G.; van Tongeren, Sean A.; Bavari, Sina

    2015-01-01

    Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development. PMID:26870818

  19. Bioenergetics profile of CD4(+) T cells in relapsing remitting multiple sclerosis subjects.

    Science.gov (United States)

    De Riccardis, Lidia; Rizzello, Antonia; Ferramosca, Alessandra; Urso, Emanuela; De Robertis, Francesca; Danieli, Antonio; Giudetti, Anna Maria; Trianni, Giorgio; Zara, Vincenzo; Maffia, Michele

    2015-05-20

    Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. There are four clinical forms of MS, the most common of which is characterized by a relapsing remitting course (RRMS). The etiology of MS is unknown, but many studies suggested that genetic, environmental and infectious agents may contribute to the development of this disease. In experimental autoimmune encephalomyelitis (EAE), the animal model for MS, it has been shown that CD4(+) T cells play a key role in MS pathogenesis. In fact, these cells are able to cross the blood-brain barrier and cause axonal damage with neuronal death. T cell activation critically depends on mitochondrial ATP synthesis and reactive oxygen species (ROS) production. Interestingly, lots of studies linked the oxidative damage arising from mitochondrial changes to neurodegenerative disorders, such as MS. Based on these evidences, this work focused on the metabolic reprogramming of CD4(+) T cells in MS subjects, being this cell population directly implicated in pathogenesis of disease, paying attention to mitochondrial function and response to oxidative stress. Such aspects, once clarified, may open new opportunities for a therapeutic metabolic modulation of MS disorder. PMID:25701681

  20. Comparative and evolutionary insights into CD4 gene across mammalian and avian taxa.

    Science.gov (United States)

    Khan, Naazneen

    2015-12-01

    The present day genetic architecture of a species bears much significance to its closely related species which is due to species-specific differences, shaped by different evolutionary forces across time scale. With the availability of whole genome sequence of several closely related species, it is now possible to infer evolutionary patterns of genes and genomes in specific lineages. To this respect, CD4 gene, primarily responsible for defensive mechanism in human, is conserved across a few taxa, and thus, comparative genomic studies could be useful for better understanding of host-pathogen biology. Comparative and evolutionary analyses were performed in eleven taxa (10 mammalian and avian) with different statistical algorithms. Phylogenetic inferences revealed recent divergence of human and chimpanzee, and pig was found to be diverged from rest of the taxa significantly. Additionally, gene length, microsatellites, and secondary structures were observed across taxa. The genetic architecture of CD4 gene and its evolutionary history in different mammalian taxa provide crucial evidence in support of the fact that this gene might have been evolving at a similar rate to other human immune system genes. Future population-based study and structural modeling would unravel the differential ability to interact with HIV virus and influence immune system in humans. PMID:26767121

  1. CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.

    Science.gov (United States)

    O'Brien, Meagan; Manches, Olivier; Wilen, Craig; Gopal, Ramya; Huq, Rumana; Wu, Vernon; Sunseri, Nicole; Bhardwaj, Nina

    2016-04-01

    Plasmacytoid dendritic cells (pDC) are innate immune cells that sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We showed previously that HIV-1 (HIV) localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. This divergent signaling may contribute to disease progression through production of pro-apoptotic and pro-inflammatory IFN and inadequate maturation of pDCs. We now demonstrate that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype. PMID:27082754

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

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    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.

  3. Naturally Occurring Self-Reactive CD4+CD25+ Regulatory T Cells: Universal Immune Code

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    Nafiseh Pakravan; Agheel Tabar Molla Hassan; Zuhair Muhammad Hassan

    2007-01-01

    Naturally occurring thymus-arisen CD4+CD25+ regulatory T (Treg) cells are considered to play a central role in self-tolerance. Precise signals that promote the development of Treg cells remain elusive, but considerable evidence suggests that costimulatory molecules, cytokines, the nature of the TCR and the niche or the context in which the T cell encounters antigen in the thymus play important roles. Analysis of TCR from Treg cells has demonstrated that a large proportion of this population has a higher avidity to self-antigen in comparison with TCR from CD4+CD25- cells and that peripheral antigen is required for their development, maintenance, or expansion. Treg cells have been shown to undergo expansion in the periphery, likely regulated by the presence of self-antigen. Many studies have shown that the involvement of Treg cells in the tolerance induction is antigen-specific, even with MHC-mismatched,in transplantation/graft versus host disease (GVHD), autoimmunity, cancer, and pregnancy. Theses studies concluded a vital role for self-reactive Treg cells in maintenance of the body integrity. Based on those studies, we hypothesize that self-reactive Treg cells are shared among all healthy individuals and recognize same self-antigens and their TCR encodes for few dominant antigens of each organ which defines the healthy self. These dominant self antigens can be regarded as "universal immune code".

  4. Spontaneous loss and alteration of antigen receptor expression in mature CD4+ T cells

    International Nuclear Information System (INIS)

    The T-cell receptor CD3 (TCR/CD3) complex plays a central role in antigen recognition and activation of mature T cells, and therefore abnormalities in the expression of the complex should induce unresponsiveness of T cells to antigen stimulus. Using flow cytometry, we detected and enumerated variant cells with loss or alteration of surface TCR/CD3 expression among human mature CD4+ T cells. The presence of variant CD4+ T cells was demonstrated by isolating and cloning them from peripheral blood, and their abnormalities can be accounted for by alterations in TCR expression such as defects of protein expression and partial protein deletion. The variant frequency in peripheral blood increased with aging in normal donors and was highly elevated in patients with ataxia telangiectasia, an autosomal recessive inherited disease with defective DNA repair and variable T-cell immunodeficiency. These findings suggest that such alterations in TCR expression are induced by somatic mutagenesis of TCR genes and can be important factors related to age-dependent and genetic disease-associated T-cell dysfunction. (author)

  5. Models of HIV-1 persistence in the CD4+ T cell compartment: past, present and future.

    Science.gov (United States)

    Tyagi, Mudit; Romerio, Fabio

    2011-12-01

    The limitations of current anti-retroviral therapies (ART) and the lack of a valid anti-HIV-1 vaccine candidate underscore the need for new therapeutic concepts aiming at the eradication of HIV-1, which represents at the same time an ideal goal and a major challenge for AIDS research. At present, this aim is unattainable due to the existence of cellular and anatomical reservoirs of persistent infection. Memory CD4(+) T cells comprise the largest pool of cells harboring silent, stably integrated HIV-1, which remains undetected by the immune system and refractory to conventional anti-retroviral drugs. The eradication of latent HIV-1 reservoirs will require new, potent and specific therapeutic strategies, which in turn must rely upon a deeper understanding of HIV-1 latency. To facilitate the advancement of our knowledge in this new area of research, several in vitro models of HIV-1 latency in CD4(+) T cells have been established. Here, we dissect and critically compare the rationale behind each experimental approach. Furthermore, we outline new avenues of research that will benefit from these models, including the push toward the development of new classes of viral eradication drugs. PMID:22211662

  6. PREVALENCE OF PULMONARY TUBERCULOSIS IN HIV POSITIVE INDIVIDUALS AND ITS ASSOCIATION WITH CD 4 COUNT

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    Sudha

    2015-02-01

    Full Text Available PURPOSE: There is grave concern regarding increase in HIV associated Tuberculosis (TB and emergence of Multi Drug Resistant (MDR and Extremely Drug Resistant (XDR TB. It is essential to know prevalence of TB in HIV patients and its association with CD 4 count. MATERIAL & METHODS: A total of 362 patients were screened for Pulmonary TB of which 85 (23.48% were diagnosed as Pulmonary TB by radiology, Ziehl Neelson (ZN smear and culture. Results: It was commoner in males (28.76%, almost equal in urban (23.64% & rural (22.45% people and more frequent in laborers (34.12%. Culture was positive in 34 (40% out of 85 Pulmonary TB patients of which 33 were M. tuberculosis and one was Rapid grower. The results of the study emphasize that co - infection of TB in HIV/AIDS patients is a concern. There is direct correlation between CD 4 counts depletion and Pulmonary TB in HIV/AIDS patient. Hence, regular monitoring of these patients is warranted.

  7. CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis.

    Science.gov (United States)

    Stromberg, Paul E; Woolsey, Cheryl A; Clark, Andrew T; Clark, Jessica A; Turnbull, Isaiah R; McConnell, Kevin W; Chang, Katherine C; Chung, Chun-Shiang; Ayala, Alfred; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

    2009-06-01

    Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, Rag-1(-/-) animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1(-/-) mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4(+) but not CD8(+), gammadelta, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1(-/-) mice. Further, adoptively transferring lymphocytes to Rag-1(-/-) mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4(+) lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality. PMID:19158156

  8. New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives.

    Science.gov (United States)

    Kanizsai, Szilvia; Ongrádi, József; Aradi, János; Nagy, Károly

    2016-07-01

    Thiolated pyrimidine derivatives have been synthetized and their antiretroviral effect against human immunodeficiency virus type 1 (HIV-1IIIB) and HIV-1 chimeric pseudovirions have been quantitatively determined in cell-based viral infectivity assays including syncytium inhibition assay as well as a single-cycle viral infection assay on HeLaCD4-LTR/ß-gal cells. Pseudotype virions prepared bearing HIV-1 envelope preference for CCR5 coreceptor, CXCR4 coreceptor or for both, respectively, with a HIV-1 core containing luciferase reporter gene were able to infect susceptible cells but are replication defective so unable to replicate in the cells . Data indicate that thiolated pyrimidine derivatives inhibited effectively virally induced cell fusion in vitro as well as infectivity of primary HIV-1IIIB strain and HIV-1 pseudovirions using chemokine receptors CCR5 or CXCR4 or both for virus entry a dose dependent manner. Inhibition was selective, depended on the pseudovirus coreceptor preference. Our results suggest that some of these sulfur containing pyrimidines interact with redoxactive -SH groups required for successful HIV entry, including a redox active disulfide in the CD4 molecule as well as -SH groups in HIV viral envelope gp120. This mode of action is unique representing a new class of potential HIV entry inhibitors. PMID:26860867

  9. CD4- and dynamin-dependent endocytosis of HIV-1 into plasmacytoid dendritic cells

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    Pritschet, Kathrin; Donhauser, Norbert; Schuster, Philipp; Ries, Moritz; Haupt, Sabrina; Kittan, Nicolai A.; Korn, Klaus [Institute of Clinical and Molecular Virology, National Reference Centre for Retroviruses, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, 91054 Erlangen (Germany); Poehlmann, Stefan [Institute of Virology, Hannover Medical School, 30625 Hannover (Germany); Holland, Gudrun; Bannert, Norbert [Robert Koch-Institute, Center for Biological Security 4, 13353 Berlin (Germany); Bogner, Elke [Institute of Virology, Charite University Hospital, 10117 Berlin (Germany); Schmidt, Barbara, E-mail: baschmid@viro.med.uni-erlangen.de [Institute of Clinical and Molecular Virology, National Reference Centre for Retroviruses, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, 91054 Erlangen (Germany)

    2012-02-20

    Chronic immune activation, triggered by plasmacytoid dendritic cell (PDC) interferon (IFN)-alpha production, plays an important role in HIV-1 pathogenesis. As the entry of HIV-1 seems to be important for the activation of PDC, we directly characterized the viral entry into these cells using immuno-electron microscopy, cellular fractionation, confocal imaging, and functional experiments. After attachment to PDC, viruses were taken up in an energy-dependent manner. The virions were located in compartments positive for caveolin; early endosomal antigen 1; Rab GTPases 5, 7 and 9; lysosomal-associated membrane protein 1. PDC harbored more virus in endocytic vesicles than CD4+ T cells (p < 0.05). Blocking CD4 inhibited the uptake of virions into cytosolic and endosomal compartments. Dynasore, an inhibitor of dynamin-dependent endocytosis, not the fusion inhibitor T-20, reduced the HIV-1 induced IFN-alpha production. Altogether, our morphological and functional data support the role of endocytosis for the entry and IFN-alpha induction of HIV-1 in PDC.

  10. CD4- and dynamin-dependent endocytosis of HIV-1 into plasmacytoid dendritic cells

    International Nuclear Information System (INIS)

    Chronic immune activation, triggered by plasmacytoid dendritic cell (PDC) interferon (IFN)-alpha production, plays an important role in HIV-1 pathogenesis. As the entry of HIV-1 seems to be important for the activation of PDC, we directly characterized the viral entry into these cells using immuno-electron microscopy, cellular fractionation, confocal imaging, and functional experiments. After attachment to PDC, viruses were taken up in an energy-dependent manner. The virions were located in compartments positive for caveolin; early endosomal antigen 1; Rab GTPases 5, 7 and 9; lysosomal-associated membrane protein 1. PDC harbored more virus in endocytic vesicles than CD4+ T cells (p < 0.05). Blocking CD4 inhibited the uptake of virions into cytosolic and endosomal compartments. Dynasore, an inhibitor of dynamin-dependent endocytosis, not the fusion inhibitor T-20, reduced the HIV-1 induced IFN-alpha production. Altogether, our morphological and functional data support the role of endocytosis for the entry and IFN-alpha induction of HIV-1 in PDC.

  11. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

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    Karen A.O. Martins

    2016-01-01

    Full Text Available Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol, MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development.

  12. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity.

    Science.gov (United States)

    Martins, Karen A O; Cooper, Christopher L; Stronsky, Sabrina M; Norris, Sarah L W; Kwilas, Steven A; Steffens, Jesse T; Benko, Jacqueline G; van Tongeren, Sean A; Bavari, Sina

    2016-01-01

    Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development. PMID:26870818

  13. Total lymphocyte count as a substitute to cd4 count in management of hiv infected individuals in resource limited society

    International Nuclear Information System (INIS)

    Pakistan is a resource limited society and gold standard parameters to monitor HIV disease activity are very costly. The objective of the study was to evaluate total lymphocyte count (TLC) as a surrogate to CD4 count to monitor disease activity in HIV/AIDS in resource limited society. Methods: This cross sectional study was carried out at HIV/AIDS treatment centre, Pakistan Institute of Medical Sciences (PIMS), Islamabad. A total of seven hundred and seventy four (774) HIV positive patients were enrolled in this study, and their CD4 count and total lymphocyte count were checked to find any correlation between the two by using Spearman ranked correlation coefficient. Results: The mean CD4 count was (434.30 ± 269.23), with minimum CD4 count of (9.00), and maximum of (1974.00). The mean total lymphocyte count (TLC) was (6764.0052 ± 2364.02) with minimum TLC (1200.00) and maximum TLC was (20200.00). Using the Pearson's correlation (r) there was a significant and positive correlation between TLC and CD4 count. (r2=0.127 and p=0.000) at 0.01 level. Conclusion: Our study showed a significant positive correlation between CD4 count and total lymphocyte count (TLC), so TLC can be used as a marker of disease activity in HIV infected patients. (author)

  14. Profound CD4+ T lymphocytopenia in human immunodeficiency virus negative individuals, improved with anti-human herpes virus treatment

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    María Lilia Diaz Betancourth

    2012-12-01

    Full Text Available 14.00 Normal 0 21 false false false ES-CO X-NONE X-NONE Lymphocytopenia and CD4+ T lymphocytopenia can be associated with many bacterial, fungal, parasite and viral infections. They can also be found in autoimmune and neoplastic diseases, common variable immu­nodeficiency syndrome, physical, psychological and traumatic stress, malnutrition and immunosuppressive therapy. Besides, they can also be brought into relation, without a known cause, with idiopathic CD4+ T lym­phocytopenia. Among viral infections, the Retrovirus, specially the human immunodeficiency virus, is the most frequently cause. However, many acute viral infections, including cytomegalovirus and Epstein Barr virus can be associated with transient lymphocytopenia and CD4+ T lymphocytopenia. As is well known, transient lymphocytopenia and CD4+ T lymphocytopenia are temporary and overcome when the disease improves. Nonetheless, severe CD4+ T Lymphocytopenia associated with chronic infections by human herpes virus has not been reported. We describe 6 cases of human immunodeficiency virus negative patients, with chronic cytomegalovirus and Epstein Barr virus infections and profound lymphocytopenia with clinical symptoms of cellular immunodeficiency. These patients improved rapidly with ganciclovir or valganciclovir treatment. We claim here that it is important to consider the chronic human herpes virus infection in the differential diag­nosis of profoundly CD4+ T lymphocytopenia etiology, when human immunodeficiency virus is absent, in order to start effective treatment and to determine, in future studies, the impact of chronic human herpes virus infection in human beings’ health.

  15. Antigen-specific and non-specific CD4+ T cell recruitment and proliferation during influenza infection

    International Nuclear Information System (INIS)

    To track epitope-specific CD4+ T cells at a single-cell level during influenza infection, the MHC class II-restricted OVA323-339 epitope was engineered into the neuraminidase stalk of influenza/A/WSN, creating a surrogate viral antigen. The recombinant virus, influenza A/WSN/OVAII, replicated well, was cleared normally, and stimulated both wild-type and DO11.10 or OT-II TCR transgenic OVA-specific CD4+ T cells. OVA-specific CD4 T cells proliferated during infection only when the OVA epitope was present. However, previously primed (but not naive) transgenic CD4+ T cells were recruited to the infected lung both in the presence and absence of the OVA323-339 epitope. These data show that, when primed, CD4+ T cells may traffic to the lung in the absence of antigen, but do not proliferate. These results also document a useful tool for the study of CD4 T cells in influenza infection

  16. Radiological features of pulmonary tuberculosis in human immunodeficiency virus-infected patients: correlation with the blood CD4 cell count

    International Nuclear Information System (INIS)

    To describe the radiological features of pulmonary tuberculosis (TB) in patients infected with human immunodeficiency virus (HIV) and its correlation with the blood CD4 cell count. We present 44 HIV+patients, 24 with CD4 cell counts of less than 200 cells/mm''3 (group A) and 20 in whom the CD4 counts surpassed this level (group B). We also assessed the chest x-ray images to determine whether or not there was any correlation with the blood CD4 cell counts. Fisher's exact test was used for the statistical study of the differences in the radiological findings in the two groups. The incidence of atypical features was significantly greater in the patients with CD4 cell counts of less than 200 cells/mm''3 (group A) than in those with CD4 counts of over 200 cells/mm''3 (group B). Among HIV+patients, those with a more intact immune status were more likely to present lung x-ray images typical of post-primary TB, with cavitary lesions in upper lobes. The group of patients in whom the immune deficiency was more marked showed a greater incidence of atypical pulmonary findings, more characteristics of primary TB. (Author)

  17. Fusion as a mediator of cytolysis in mixtures of uninfected CD4+ lymphocytes and cells infected by human immunodeficiency virus

    International Nuclear Information System (INIS)

    The authors describe an unusual type of cytopathology in which uninfected CD4+ (helper/inducer) cells (cells expressing the human leukocyte antigen CD4) interact with cells persistently infected with the human immunodeficiency virus (HIV). Prior antigenic stimulation was not required, since CD4+ cells taken either from healthy persons without anti-HIV antibodies or from individuals with anti-HIV antibodies were capable in inducing cytolysis. Neither CD8+ (suppressor/cytotoxic) nor CD16+ (natural killer) cells mediated the reaction. Light microscopic and autoradiographic studies revealed that, prior to cytolysis, multinucleated giant cells were formed from fusions between HIV-infected cells and large numbers of uninfected CD4+ lymphocytes. These data may explain the paradox that exists in vivo in which a dramatic depletion of CD4+ lymphocytes occurs in the presence of a small number of HIV-infected CD4+ cells. These new insights into the pathogenesis of acquired immunodeficiency syndrome (AIDS) may lead to future therapeutic strategies

  18. Decrease of CD4+ T lymphocytes in patients with H1N1 in early stage and its clinical significances

    International Nuclear Information System (INIS)

    Objective: To observe the change of CD4+ T Lymphocytes in patients with H1N1 at early stage and figure out its clinical significances on the progress and therapeutic selection of H1N1. Methods: The absolute counts of T lymphocyte subset from the peripheral blood samples of 48 H1N1 patients in first ten days' duration were detected by flow cytometry, and the serial chest CT examinations were performed. Results: In all 48 clinical cases, 28 cases were in normal range of CD4+ lymphocyte absolute count, whose pulmonary lesions were limited and illness condition stayed in the stability, they didn't need steroid. In the other 20 cases with low level of CD4+, 4 cases' illness presented the progressive development and needed to be treated with steroid and 16 cases with lightly decreased CD4+ level which had a stable condition without treatment with steroid. The result of Pearson correlation analysis showed that there were negative correlations between absolute count of CD4+ cells and pulmonary lesions (r=-0.299, P+ cell absolute count of H1N1 patients at early stage indicates the worse condition of pulmonary lesions. The patients with remarkable decrease of CD4+ lymphocytes are in need of treatment with steroid. (authors)

  19. Enumeration of CD4 and CD8 T-cells in HIV infection in Zimbabwe using a manual immunocytochemical method

    DEFF Research Database (Denmark)

    Gomo, E; Ndhlovu, P; Vennervald, B J; Nyazema, N; Friis, Henrik

    2001-01-01

    OBJECTIVES: To enumerate CD4 and CD8 T-cells using the simple and cheap immuno-alkaline phosphatase (IA) method and to compare it with flow cytometry (FC); and to study the effects of duration of sample storage on the IA method results. DESIGN: Method comparison study. SETTING: Blair Research...... Laboratory, Harare, Zimbabwe. SUBJECTS: 41 HIV positive and 11 HIV negative men and women from Harare participating in HIV studies at Blair Research Laboratory, Zimbabwe. MAIN OUTCOME MEASURES: CD4 and CD8 T-cell counts by FC and the IA method. RESULTS: The IA method and FC were highly correlated for CD4...... counts (Spearman rs = 0.91), CD4 percentage (rs = 0.84), CD8 count (rs = 0.83), CD8 percentage (rs = 0.96) and CD4/CD8 ratio (rs = 0.89). However, CD4 cell counts and percentage measured by the IA method were (mean difference +/- SE) 133 +/- 24 cells/microL [corrected] and 6.7 +/- 1.1% higher than those...

  20. Oral vaccination with lipid-formulated BCG induces a long-lived, multifunctional CD4(+ T cell memory immune response.

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    Lindsay R Ancelet

    Full Text Available Oral delivery of BCG in a lipid formulation (Liporale™-BCG targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4(+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4(+ T cell response, evident by the detection of effector CD4(+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4(+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4(+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4(+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines.

  1. A specific assay measuring binding of 125I-Gp 120 from HIV to T4+/CD4+ cells

    International Nuclear Information System (INIS)

    The HIV (HTLV-III) envelope glycoprotein, Gp120, was isolated from virus-infected tissue culture cells using affinity chromatography. A radioimmunoassay was developed to determine the degree of iodinated Gp120 to target CD4+ (T4+) cells. 125I-Gp120 could be shown to selectively bind to CD4+ cells only. The Gp120 remained bound to these cells after repeated washes. Monoclonal anti-CD4 antibodies block the binding of Gp120 to CD4+ cells. Monoclonal antibodies to other cell surface components do not interfere with 125I-Gp120 binding. All IgG antibodies from HIV seropositive donors tested block 125I-GP120 binding, though with variable titers. The authors believe that this assay provides further proof for the use of CD4 (T4) as a component of the receptor for HIV. It represents a safe, objective and sensitive method for the analysis of Gp120-CD4 interactions, as well as the potential of antibodies to interfere with this binding. (Auth.)

  2. Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4(+) effector memory T cells.

    Science.gov (United States)

    Zhou, Fang; Zhang, Guang-Xian; Rostami, Abdolmohamad

    2016-02-01

    CD4(+) memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4(+) memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4(+) effector memory T cells in vitro and in vivo. Simultaneously, intravenous transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4(+) T cells, not central memory CD4(+) T cells, which play a major role in chronic inflammatory responses in mice with EAE. Intravenous transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4(+) effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo. PMID:26111522

  3. Tuberculosis-HIV Coinfection: The Relationship Between Manifestation Of Tuberculosis And The Degree Of Immunosuppression (CD4 Counts

    Directory of Open Access Journals (Sweden)

    C K Ong

    2008-12-01

    Full Text Available The incidence of tuberculosis (TB iscurrently increasing. HIV induced immuno-suppressionmodifies the clinical presentation of TB. Our aim is todetermine the differences in clinical presentation ofHIV-TB co-infection based on their CD4 counts.This retrospective study looked at cases of adult activeTB and HIV-1 co-infection treated in Penang Hospitalfrom January 2004 to December 2005. Of the820 patients treated for active TB, HIV-1 seropositivityrate was 12.6% (103 patients. Majority of HIV-1co-infected patients presented with prolonged insidiousand non-specific symptoms like weight loss, fever andnight sweats. The clinical presentation of TB dependedon the stage of HIV-1 infection and associateddegree of immunodeficiency. Compared to the lessimmuno-compromised HIV-1 and TB co-infectedpopulation (CD4 > 200/mm3, patients with CD4counts ² 200 are more likely to have atypical chestradiographs (P = 0.009. During active TB, theMantoux test was positive in 12 (14.5% HIV-1 infectedpatients with a CD4 counts ² 200/mm3 and in 16 (80%of those with CD4 counts > 200/mm3 (P = 0.0001.In our series, the AFB smear / AFB culture and typeof TB did not show obvious correlation withCD4 counts. Therefore to diagnose TB in severelyimmuno-compromised HIV patients, we need to have ahigh index of suspicion.

  4. HIV-Tuberculosis: A Study of Chest X-Ray Patterns in Relation to CD4 Count

    Directory of Open Access Journals (Sweden)

    Mahesha Padyana

    2012-01-01

    Full Text Available Background : Fight against human immunodeficiency virus (HIV is incomplete without addressing problems associated with difficult diagnosis of tuberculosis in HIV-Tuberculosis coinfected patients. Chest X-ray is a primary tool to evaluate tuberculosis in HIV. Aim: To assess and compare various radiological patterns of pulmonary tuberculosis in HIV patients and compare these patterns in relation to CD4 counts. Materials and Methods : Prospective cohort study was conducted in a tertiary hospital in South India from September 2009 to July 2011 with 200 HIV positive patients. WHO guidelines were used for diagnosis of HIV and tuberculosis. Results : 27% of the patients had sputum positive pulmonary tuberculosis, with higher incidence (33% among CD4 less than 200 as compared to CD4 more than 200 (14%. Infiltration (39% followed by consolidation (30%, cavity (11%, and lymphadenopathy (9% seen with CD4 less than 200. Infiltration (37.5% followed by cavity (25% and miliary (25% with CD4 above 200. Bilateral (68.5% and mid and lower zones or all zone involvement more commonly seen. Conclusion : In patients with CD4 lower than 200 noncavitory infiltration and consolidation predominated. Involvement of lungs was atypical; diffuse or mid and lower zone involvement than classical upper lobe involvement. A high index of suspicion is necessary for the accurate and timely diagnosis of tuberculosis in HIV positive patients.

  5. Profound CD4+ T lymphocytopenia in human immunodeficiency virus negative individuals, improved with anti-human herpes virus treatment

    Directory of Open Access Journals (Sweden)

    Díaz Betancourt, María Lilia

    2012-12-01

    Full Text Available Lymphocytopenia and CD4+ T lymphocytopenia can be associated with many bacterial, fungal, parasite and viral infections. They can also be found in autoimmune and neoplastic diseases, common variable immunodeficiency syndrome, physical, psychological and traumatic stress, malnutrition and immunosuppressive therapy. Besides, they can also be brought into relation, without a known cause, with idiopathic CD4+ T lymphocytopenia. Among viral infections, the Retrovirus, specially the human immunodeficiency virus, is the most frequently cause. However, many acute viral infections, including cytomegalovirus and Epstein Barr virus can be associated with transient ymphocytopenia and CD4+ T lymphocytopenia. As is well known, transient ymphocytopenia and CD4+ T lymphocytopenia are temporary and overcome when the disease improves. Nonetheless, severe CD4+ T Lymphocytopenia associated with chronic infections by human herpes virus has not been reported. We describe 6 cases of human immunodeficiency virus negative patients, with chronic cytomegalovirus and Epstein Barr virus infections and profound lymphocytopenia with clinical symptoms of cellular immunodeficiency. These patients improved rapidly with ganciclovir or valganciclovir treatment. We claim here that it is important to consider the chronic human herpes virus infection in the differential diagnosis of profoundly CD4+ T lymphocytopenia etiology, when human mmunodeficiency virus is absent, in order to start effective treatment and to determine, in future studies, the impact of chronic human herpes virus infection in human beings’ health

  6. IL-17-expressing CD4⁺ and CD8⁺ T lymphocytes in human toxoplasmosis.

    Science.gov (United States)

    Silva, Jéssica Líver Alves; Rezende-Oliveira, Karine; da Silva, Marcos Vinicius; Gómez-Hernández, César; Peghini, Bethânea Crema; Silva, Neide Maria; Mineo, José Roberto; Rodrigues Júnior, Virmondes

    2014-01-01

    This study aimed to measure the synthesis of Th1 and Th2 cytokines by mononuclear cells after culture with live T. gondii and identified Th17 (CD4(+)) and Tc17 (CD8(+)) cells in toxoplasma-seronegative and toxoplasma-seropositive parturient and nonpregnant women. Cytometric bead arrays were used to measure cytokine levels (IL-2, TNF-α, IFN-γ, IL-4, IL-5, and IL-10); immunophenotyping was used to characterize Th17 and Tc17 cells, and the cells were stained with antibodies against CD4(+) and CD8(+) T cells expressing IL-17. The addition of tachyzoites to cell cultures induced the synthesis of IL-5, IL-10, and TNF-α by cells from seronegative parturient women and of IL-5 and IL-10 by cells from seropositive, nonpregnant women. We observed a lower level of IL-17-expressing CD4(+) and CD8(+) T lymphocytes in cultures of cells from seronegative and seropositive parturient and nonpregnant women that were stimulated with tachyzoites, whereas analysis of the CD4(+) and CD8(+) T cell populations showed a higher level of CD4(+) T cells compared with CD8(+) T cells. These results suggest that the cytokine pattern and IL-17-expressing CD4(+) and CD8(+) T lymphocytes may have important roles in the inflammatory response to T. gondii, thus contributing to the maintenance of pregnancy and control of parasite invasion and replication. PMID:25214715

  7. CD4 + CD25 + Treg cell separate, phenotype identity and Foxp3 gene expression identity%CD4+CD25+Treg细胞的分选、表型鉴定及Foxp3表达鉴定

    Institute of Scientific and Technical Information of China (English)

    韩文杰; 史艳侠

    2010-01-01

    目的 为验证从C57BL/6小鼠脾脏中分离出高纯度CD4+CD25+Treg细胞及证实CD4+CD25+Treg细胞中Foxp3基因的表达.方法 使用免疫磁珠分选出CD4+CD25+Treg细胞,流式细胞仪检测纯度;使用TRIZOL抽提Foxp3基因mRNA,使用RT-PCR方法逆转录出Foxp3基因的cDNA.结果 从C57BL/6小鼠脾脏中分离出了纯度达到90%CD4+CD25+Treg.进一步应用RT-PCR技术克隆出Foxp3的cDNA,通过凝胶电泳证实了克隆出了Foxp3的cDNA.结论 使用免疫磁珠方法能够分离出C57BL/6小鼠CD4+CD25+Treg细胞,并进行了Foxp3基因表达的鉴定.%Objective To confirm high purity CD4 + CD25 + Treg cells can be separated from the spleen of C57BL/6 mice and Foxp3 gene can be express in CD4 + CD25 + Treg cells.Methods CD4 + CD25 + Treg cells are separated with immunomagnetic beads,and purity is detected by flow cytometry.Foxp3 gene mRNA is extracted using TRIZOL.Foxp3 gene cDNA is reverse transcription using RT-PCR technology.Results This study separated CD4 + CD25 + Treg cell of 90% purity from the spleen of C57BI/6 mice,to advance used technology of RT-PCR to make the clone of Foxp3 gene cDNA,and confirmed it is the cDNA of foxp3.Conclusion This study CD4 + CD25 + Treg cell can be separated from the spleen of C57BL/6 mice with immnnomagnetic beads,and identified foxp3 gene expression.

  8. Immunity to experimental Salmonella typhimurium infections in rats. Transfer of immunity with primed CD45RC+ and CD45RC- CD4 T-cell subpopulations

    DEFF Research Database (Denmark)

    Thygesen, P; Christensen, H B; Hougen, H P;

    1996-01-01

    The protective effect of primed CD4 T cells against a lethal dose of Salmonella typhimurium was studied in Lewis rats. Primed CD4 T cells were obtained by inoculating Lewis rats with a non-lethal dose of S. typhimurium. Four weeks after the infection, spleen CD4 T cells were separated by antibody...

  9. Determinants of CD4 counts among HIV-Negative ethiopians: Role of body mass index, gender, cigarette smoking, khat (Catha edulis) chewing, and possibly altitude?

    NARCIS (Netherlands)

    Abuye, C.; Tsegaye, A.; West, C.E.; Versloot, P.; Sanders, E.J.; Wolday, D.; Hamann, D.; Wit, De T.F.R.; Fontanet, A.L.

    2005-01-01

    To study the determinants of CD4% and CD4 counts among HIV-negative Ethiopians, and to identify factors susceptible to explain the low CD4 counts observed among Ethiopian subjects. Cohort studies among factory workers in Akaki and Wonji, Ethiopia. Clinical and laboratory examinations, including dete

  10. File list: InP.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: InP.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: DNS.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. File list: Pol.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. File list: ALL.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. File list: NoD.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  16. File list: DNS.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  17. File list: Unc.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  18. File list: Pol.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: Unc.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: Unc.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: Unc.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  2. File list: NoD.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  3. File list: InP.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: ALL.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  5. File list: DNS.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: ALL.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: Pol.Bld.50.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: Pol.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: InP.Bld.20.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: ALL.Bld.10.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: DNS.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: NoD.Bld.05.AllAg.CD4_CD8_double_negative_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  13. Different Immunological Phenotypes Associated with Preserved CD4+ T Cell Counts in HIV-Infected Controllers and Viremic Long Term Non-Progressors

    DEFF Research Database (Denmark)

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

    2013-01-01

    HIV-infected controllers control viral replication and maintain normal CD4+ T cell counts. Long Term Non-Progressors (LTNP) also maintain normal CD4+ T cell counts, but have on-going viral replication. We hypothesized that different immunological mechanisms are responsible for preserved CD4+ T cell...... counts in controllers and LTNP....

  14. File list: Unc.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. File list: DNS.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Bld.20.AllAg.CD4_CD8_double_positive_cells mm9 DNase-seq Blood CD4 CD8 double positive... cells http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/DNS.Bld.20.AllAg.CD4_CD8_double_positive_cells.bed ...

  16. File list: His.Bld.50.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  17. File list: DNS.Bld.50.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  18. File list: His.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: NoD.Bld.10.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: Pol.Bld.10.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: Unc.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  2. File list: ALL.Bld.50.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  3. File list: DNS.Bld.10.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  4. File list: NoD.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  5. File list: NoD.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  7. File list: ALL.Bld.10.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  8. File list: His.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  9. File list: ALL.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  10. File list: Pol.Bld.20.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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    Full Text Available Pol.Bld.20.AllAg.CD4_CD8_double_positive_cells mm9 RNA polymerase Blood CD4 CD8 double positive... cells SRX063926,SRX099398,SRX099388 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Pol.Bld.20.AllAg.CD4_CD8_double_positive_cells.bed ...

  11. File list: Unc.Bld.50.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  13. File list: Pol.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  14. File list: DNS.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

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  15. File list: ALL.Bld.05.AllAg.CD4_CD8_double_positive_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.05.AllAg.CD4_CD8_double_positive_cells mm9 All antigens Blood CD4 CD8 double positive...X692962,SRX692956 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Bld.05.AllAg.CD4_CD8_double_positive_cells.bed ...

  16. Is Job Enrichment Really Enriching?

    OpenAIRE

    Robert D. Mohr; Cindy Zoghi

    2006-01-01

    This study uses a survey of Canadian workers with rich, matched data on job characteristics to examine whether “enriched” job design, with features like quality circles, feedback, suggestion programs, and task teams, affects job satisfaction. We identify two competing hypotheses on the relationship between enriched jobs and job satisfaction. The “motivation hypothesis,” implies that enrichment will generally increase satisfaction and the “intensification hypothesis,” implies that enrichment m...

  17. An integrated tiered service delivery model (ITSDM based on local CD4 testing demands can improve turn-around times and save costs whilst ensuring accessible and scalable CD4 services across a national programme.

    Directory of Open Access Journals (Sweden)

    Deborah K Glencross

    Full Text Available The South African National Health Laboratory Service (NHLS responded to HIV treatment initiatives with two-tiered CD4 laboratory services in 2004. Increasing programmatic burden, as more patients access anti-retroviral therapy (ART, has demanded extending CD4 services to meet increasing clinical needs. The aim of this study was to review existing services and develop a service-model that integrated laboratory-based and point-of-care testing (POCT, to extend national coverage, improve local turn-around/(TAT and contain programmatic costs.NHLS Corporate Data Warehouse CD4 data, from 60-70 laboratories and 4756 referring health facilities was reviewed for referral laboratory workload, respective referring facility volumes and related TAT, from 2009-2012.An integrated tiered service delivery model (ITSDM is proposed. Tier-1/POCT delivers CD4 testing at single health-clinics providing ART in hard-to-reach areas (350-1500 tests/day, serving ≥ 200 health-clinics. Tier-6 provides national support for standardisation, harmonization and quality across the organization.The ITSDM offers improved local TAT by extending CD4 services into rural/remote areas with new Tier-3 or Tier-2/POC-Hub services installed in existing community laboratories, most with developed infrastructure. The advantage of lower laboratory CD4 costs and use of existing infrastructure enables subsidization of delivery of more expensive POC services, into hard-to-reach districts without reasonable access to a local CD4 laboratory. Full ITSDM implementation across 5 service tiers (as opposed to widespread implementation of POC testing to extend service can facilitate sustainable 'full service coverage' across South Africa, and save>than R125 million in HIV/AIDS programmatic costs. ITSDM hierarchical parental-support also assures laboratory/POC management, equipment maintenance, quality control and on-going training between tiers.

  18. Detection and Significance of CD4+CD25+CD127dim Regulatory T Cells in Individuals with Severe Aplastic Anemia

    Directory of Open Access Journals (Sweden)

    Weiwei Qi

    2015-09-01

    Full Text Available Objective: To investigate the relationship between CD4+CD25+CD127dim regulatory T cells (Tregs and immune imbalance in acquired severe aplastic anemia (SAA. Materials and Methods: The quantity of CD4+CD25+CD127dim Tregs in 44 SAA patients and 23 normal controls was measured by flow cytometry. Correlations between Tregs and T cell subsets, dendritic cell (DC subsets, granulocyte counts, and percentage of reticulocytes (RET% were analyzed. Results: The percentage of CD4+CD25+CD127dim Tregs in peripheral blood lymphocytes (PBLs of untreated patients was lower than in recovery patients and normal controls (0.83±0.44% vs. 2.91±1.24% and 2.18±0.55%, respectively, p<0.05. The percentage of CD4+CD25+CD127dim Tregs in CD4+ T lymphocytes of recovery patients was higher than that of untreated patients and normal controls (9.39±3.51% vs. 7.61±5.3% and 6.83±1.4%, respectively, p<0.05. The percentage of CD4+ T lymphocytes in PBLs of untreated patients was lower than in recovery patients and normal controls (13.55±7.37% vs. 31.82±8.43% and 32.12±5.88%, respectively, p<0.05. T cell subset (CD4+/CD8+ ratio was 0.41±0.24 in untreated patients, which was lower than in recovery patients (1.2±0.4 and normal controls (1.11±0.23 (p<0.05. DC subset (myeloid DC/plasmacytoid DC ratio, DC1/DC2 ratio was 3.08±0.72 in untreated patients, which was higher than in recovery patients (1.61±0.49 and normal controls (1.39±0.36 (p<0.05. The percentage of CD4+CD25+CD127dim Tregs in PBLs was positively associated with T cell subset (r=0.955, p<0.01 and negatively associated with DC subset (r=-0.765, p<0.01. There were significant positive correlations between CD4+CD25+CD127dim Tregs/PBL and granulocyte counts and RET% (r=0.739 and r=0.749, respectively, p<0.01. Conclusion: The decrease of CD4+CD25+CD127dim Tregs in SAA patients may cause excessive functioning of T lymphocytes and thus lead to hematopoiesis failure in SAA.

  19. Nef functions in BLT mice to enhance HIV-1 replication and deplete CD4+CD8+ thymocytes

    Directory of Open Access Journals (Sweden)

    Zou Wei

    2012-05-01

    Full Text Available Abstract Background The outcome of untreated HIV-1 infection is progression to AIDS and death in nearly all cases. Some important exceptions are the small number of patients infected with HIV-1 deleted for the accessory gene, nef. With these infections, disease progression is entirely suppressed or greatly delayed. Whether Nef is critical for high levels of replication or is directly cytotoxic remains controversial. The major problem in determining the role of Nef in HIV/AIDS has been the lack of tractable in vivo models where Nef’s complex pathogenic phenotype can be recapitulated. Results Intravenous inoculation (3000 to 600,000 TCIU of BLT humanized mice with HIV-1LAI reproducibly establishes a systemic infection. HIV-1LAI (LAI replicates to high levels (peak viral load in blood 8,200,000 ± 1,800,000 copies of viral RNA/ml, range 3,600,000 to 20,400,000; n = 9 and exhaustively depletes CD4+ T cells in blood and tissues. CD4+CD8+ thymocytes were also efficiently depleted but CD4+CD8- thymocytes were partially resistant to cell killing by LAI. Infection with a nef-deleted LAI (LAINefdd gave lower peak viral loads (1,220,000 ± 330,000, range 27,000 to 4,240,000; n = 17. For fourteen of seventeen LAINefdd-infected mice, there was little to no loss of either CD4+ T cells or thymocytes. Both LAI- and LAINefdd-infected mice had about 8% of total peripheral blood CD8+ T cells that were CD38+HLA-DR+ compared dd-infected mice that lost CD4+ T cells received 600,000 TCIU. All three exhibited peak viral loads over 3,000,000 copies of LAINefdd RNA/ml. Over an extended time course, substantial systemic CD4+ T cell loss was observed for the three mice, but there was no loss of CD4+CD8+ or CD4+CD8- thymocytes. Conclusion We conclude Nef is necessary for elevated viral replication and as a result indirectly contributes to CD4+ T cell killing. Further, Nef was not necessary for the activation of peripheral blood CD8+ T cells following

  20. Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa.

    Directory of Open Access Journals (Sweden)

    Alastair Heffernan

    Full Text Available Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3% of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness.

  1. Uranium enrichment

    International Nuclear Information System (INIS)

    GAO was asked to address several questions concerning a number of proposed uranium enrichment bills introduced during the 100th Congress. The bill would have restructured the Department of Energy's uranium enrichment program as a government corporation to allow it to compete more effectively in the domestic and international markets. Some of GAO's findings discussed are: uranium market experts believe and existing market models show that the proposed DOE purchase of a $750 million of uranium from domestic producers may not significantly increase production because of large producer-held inventories; excess uranium enrichment production capacity exists throughout the world; therefore, foreign producers are expected to compete heavily in the United States throughout the 1990s as utilities' contracts with DOE expire; and according to a 1988 agreement between DOE's Offices of Nuclear Energy and Defense Programs, enrichment decommissioning costs, estimated to total $3.6 billion for planning purposes, will be shared by the commercial enrichment program and the government

  2. Histone modifications of Notch1 promoter affect lung CD4+ T cell differentiation in asthmatic rats.

    Science.gov (United States)

    Cui, Z-L; Gu, W; Ding, T; Peng, X-H; Chen, X; Luan, C-Y; Han, R-C; Xu, W-G; Guo, X-J

    2013-01-01

    Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4+ T cells. Chromatin immunoprecipitation analysis showed that the acetylation levels of total H3, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notch1 gene promoter were increased significantly in asthmatic lung CD4+ T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4+ T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, IL-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-κB and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notch1 promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma. PMID:23755752

  3. 白癜风患者外周血CD4+CD25+调节性T细胞的检测%Detection of peripheral CD4+CD25+ regulatory T lymphocytes in patients with vitiligo

    Institute of Scientific and Technical Information of China (English)

    白明辉; 王竞; 涂彩霞; 张蕴颖; 刘敏; 李国艳; 钟良瑞

    2009-01-01

    Objective To determine the level of peripheral CD4+CD25+ regulatory T lymphocytes in patients with vitiligo at different stages and to study its relationship with the development of vitiligo. Methods Blood samples were collected from 34 outpatients with vitiligo, including 19 cases of progressive vitiligo and 15 cases of stable vitiligo, as well as from 20 normal human controls. Flow cytometry was used to detect the levels of peripheral CD4+ and CD4+CD25+ T lymphocytes in these samples. Results Compared with the controls, the percentage of CD4+CD25+ regulatory T lymphoeytes in peripheral lymphocytes was significantly lower in patients with progressive vitiligo than those in patients with stable vitiligo and normal human con-trois [(2.43±0.30)% vs (3.49±0.39)% and (3.34±0.24)%, both P <0.05], but no significant difference was found between patients with stable vitiligo and normal human controls (P>0.05). A significantly nega-tive correlation was observed between the percentage of CD4+CD25+ regulatory T lymphocytes and lesion area in patients with progressive vitiligo (r = -0.48, P <0.05), but not in patients with stable vitiligo (P >0.05). There was no significant correlation between the course of disease and the percentage of peripheral CD4+CD25+ regulatory T lymphocytes in patients with progressive vitiligo or stable vitiligo (both P > 0.05). Conclusion There is an abnormal proportion of peripheral CD4+CD25+ regulatory T lymphocytes in patients with vitiligo, which may be related to the development of vitiligo.%目的 检测不同病期白癜风患者外周血CD4+CD25+调节性T细胞水平,探讨其与白癜风发病的关系.方法 白癜风患者34例,进展期19例,稳定期15例.通过流式细胞仪对不同病期白癜风患者外周血CD4+、CD4+CD25+T细胞水平进行检测,并与20例正常人比较.结果 进展期患者外周血中CD4+CD25+调节性T细胞占外周血淋巴细胞的表达率低于正常对照组(P<0.05);稳定期患者与正

  4. Nuclear localization of Vpr is crucial for the efficient replication of HIV-1 in primary CD4+ T cells

    International Nuclear Information System (INIS)

    The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr appears to make a substantial contribution to the replication of HIV-1 in established T cell lines when HIV-1 is present at very low multiplicities of infection. However, the role of Vpr in viral replication in primary CD4+ T cells remains to be clarified. In this study, we generated a panel of viruses that encoded mutant forms of Vpr that lacked either the ability to accumulate in the nucleus and induce G2 arrest or the ability to induce apoptosis, which has been shown to occur independently of G2 arrest of the cell cycle. We demonstrate here that the nuclear localization of Vpr and consequent G2 arrest but not the induction of apoptosis by Vpr are important for viral replication in primary CD4+ T cells at both high and low multiplicities of infection. Viruses that encoded mutant forms of Vpr that failed to be imported into the nucleus in the presence of cytoplasmic extracts from primary CD4+ T cells in an in vitro nuclear import assay replicated at drastically reduced rates. Thus, Vpr might be a key regulator of the viral nuclear import process during infection in primary CD4+ T cells. By contrast, a mutant form of Vpr that exhibited diffuse cytosolic staining exclusively in an immunofluorescence assay of HeLa cells and was not imported into nucleus by the cytosol from HeLa cells was effectively imported into the nucleus by cytosol from primary CD4+ T cells. This Vpr mutant virus replicated well in primary CD4+ T cells, indicating that cellular factors in primary CD4+ T cells are indispensable for the accumulation of Vpr in the nucleus and, thus, for viral replication. Our results suggest that the nuclear import of Vpr might be a good target in efforts to block the early stages of replication of HIV-1

  5. Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.

    Science.gov (United States)

    Liu, Haibo; Gao, Wei; Yuan, Jie; Wu, Chaoneng; Yao, Kang; Zhang, Li; Ma, Leilei; Zhu, Jianbing; Zou, Yunzeng; Ge, Junbo

    2016-02-01

    CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-γ and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs. PMID:26746143

  6. A false expression of CD8 antigens on CD4+ T cells in a routine flow cytometry analysis.

    Directory of Open Access Journals (Sweden)

    Danuta Kowalczyk

    2006-09-01

    Full Text Available The two-colour flow cytometry method applied in a routine enumeration of peripheral blood T lymphocyte subsets reveals that in some patients the entire population of CD4+ lymphocytes seems to express CD8 determinants as well. However, expression of the CD8 antigens on the cell surface is much lower in comparison with typical CD8+ cells. Moreover, in one-colour staining with an anti-CD8 antibody, cells with weak CD8 expression are not observed and only one typical population of CD8+ lymphocytes is seen. Investigating this phenomenon, we showed that after washing patient cells in RPMI before CD4/CD8 staining, the CD4+ T cell population did not show CD8 "co-expression". These results suggest that CD4+ lymphocytes, which seem to co-express CD8 antigen, in fact do not have this antigen on their surface. Moreover, after the addition of patient plasma to healthy donor cells prior to CD4/CD8 staining, a weak CD8 expression on normal CD4+ cells was noticed. Therefore we can assume that the agent(s causing this phenomenon is/are present in the plasma of some patients. Altogether, these observations suggest that this phenomenon is nonspecific and probably results from cross-linking of anti-CD8 mAbs with anti-CD4 mAbs caused by factor(s present in plasma of some patient. However, identification of that/these factor(s requires further research.

  7. Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m Anti-CD4-mAb fragment scintigraphy

    International Nuclear Information System (INIS)

    Purpose: T-cell-located CD4 antigen represents one of the therapeutic targets in rheumatoid arthritis (RA). However, up to now there is no established imaging tool to visualize this target in vivo. The aim of our study was to assess the safety and tolerability of a technetium-99 m labelled murine anti-human CD4 IgG1-Fab fragment ([99mTc]-anti-CD4-Fab, [99mTc]-EP1645) in patients with active synovitis due to RA, and to evaluate its potential as a marker of disease activity. Methods: In the present phase I proof of principle study five patients with RA were examined. Planar scans of the whole body, hands, and feet were taken 30 min up to 24 h after application of 550 ± 150 MBq [99mTc]-anti-CD4-Fab, followed by visual analyses, comparison with clinical data in 68 joints per patient and semiquantitative analysis of hand and wrist joints. Results: Neither infusion related adverse events nor adverse events during follow up were observed. No increase in human anti-murine antibody titres was seen. All patients had positive scans in almost 70% of clinically affected joints. Positive scans were also found in 8% of joints without evidence of swelling or tenderness. Conclusion: Scintigraphy with [99mTc]-anti-CD4-Fab is a promising technique for evaluation of inflammatory activity in patients with RA, pre-therapeutical evaluation of CD4 status and therapy control. Tracer uptake in clinically inconspicuous joints strongly indicates diagnostic potential of [99mTc]-anti-CD4-Fab. Whether this technique is eligible as a prognostic factor in RA needs to be analysed in further studies as well as the pathophysiological background of clinically affected joints lacking tracer uptake

  8. Relationship between antiretrovirals used as part of a cART regimen and CD4 count increases in patients with suppressed viremia

    DEFF Research Database (Denmark)

    Mocroft, A; Phillips, A; Ledergerber, B; Katlama, C; Chiesi, A; Goebel, F; Knysz, B; Antunes, F; Reiss, P; Lundgren, Jens Dilling

    2006-01-01

    BACKGROUND: It is unknown if the CD4 cell count response differs according to antiretroviral drugs used in combination antiretroviral therapy (cART) in patients with maximal virological suppression [viral load (VL) < 50 copies/ml]. OBJECTIVES: To compare the change in CD4 cell count over...... from starting cART, age, CD4 at first VL < 50 copies/ml, prior antiretroviral treatment, and change in CD4 cell count since starting cART. RESULTS: We studied 28418 instances of VL < 50 copies/ml in 4041 patients. The mean annual change in CD4 cell count was +45.5/microl [95% confidence interval (CI...

  9. Ex vivo restimulation of human PBMC expands a CD3+CD4-CD8- γδ+ T cell population that can confound the evaluation of CD4 and CD8 T cell responses to vaccination.

    Science.gov (United States)

    Sedgmen, B J; Papalia, L; Wang, L; Dyson, A R; McCallum, H A; Simson, C M; Pearse, M J; Maraskovsky, E; Hung, D; Eomois, P P; Hartel, G; Barnden, M J; Rockman, S P

    2013-01-01

    The measurement of vaccine-induced humoral and CD4(+) and CD8(+) cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3(+)CD4(-)CD8(-) γδ (+) T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3(+)CD4(-)CD8(-) γδ (+) T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4(+) and CD8(+) immune responses following vaccination, the CD3(+)CD4(-)CD8(-) γδ (+) T cells are either excluded or separately enumerated from the overall frequency determination. PMID:24066003

  10. Ex Vivo Restimulation of Human PBMC Expands a CD3+CD4−CD8−γδ+ T Cell Population That Can Confound the Evaluation of CD4 and CD8 T Cell Responses to Vaccination

    Science.gov (United States)

    Sedgmen, B. J.; Papalia, L.; Wang, L.; Dyson, A. R.; McCallum, H. A.; Simson, C. M.; Pearse, M. J.; Maraskovsky, E.; Hung, D.; Eomois, P. P.; Hartel, G.; Barnden, M. J.; Rockman, S. P.

    2013-01-01

    The measurement of vaccine-induced humoral and CD4+ and CD8+ cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3+CD4−CD8−γδ+ T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3+CD4−CD8−γδ+ T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4+ and CD8+ immune responses following vaccination, the CD3+CD4−CD8−γδ+ T cells are either excluded or separately enumerated from the overall frequency determination. PMID:24066003

  11. Ex Vivo Restimulation of Human PBMC Expands a CD3+CD4-CD8-γδ+ T Cell Population That Can Confound the Evaluation of CD4 and CD8 T Cell Responses to Vaccination

    Directory of Open Access Journals (Sweden)

    B. J. Sedgmen

    2013-01-01

    Full Text Available The measurement of vaccine-induced humoral and CD4+ and CD8+ cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3+CD4-CD8-γδ+ T cell population in the peripheral blood of 90/610 (15% healthy subjects. The appearance of CD3+CD4-CD8-γδ+ T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4+ and CD8+ immune responses following vaccination, the CD3+CD4-CD8-γδ+ T cells are either excluded or separately enumerated from the overall frequency determination.

  12. Effects of PMA on CD4 expression on T-helper surface in vitro%佛波脂对体外培养Th细胞表面CD4分子表达的影响

    Institute of Scientific and Technical Information of China (English)

    叶卫东; 张循善; 孙小梅; 连莉; 徐建华; 李庆

    2005-01-01

    目的探索佛波脂(PMA)对Th细胞表面CD4分子表达的影响.方法用荧光标记的抗CD3/4/8抗体同经10、15、20、25ng/mL的PMA和1μg/mL的Ionomycin刺激培养2、3、4 h的正常人外周全血细胞中的Th细胞上的CD4分子结合,溶血后用流式细胞仪检测CD4通道的荧光强度(MFI).结果CD4通道的MFI随PMA质量浓度的升高和刺激时间的延长而降低.结论Th细胞表面CD4分子在刺激培养过程中随PMA质量浓度的升高和刺激时间的延长而减少.

  13. Uranium enrichment

    International Nuclear Information System (INIS)

    Canada is the world's largest producer and exporter of uranium, most of which is enriched elsewhere for use as fuel in LWRs. The feasibility of a Canadian uranium-enrichment enterprise is therefore a perennial question. Recent developments in uranium-enrichment technology, and their likely impacts on separative work supply and demand, suggest an opportunity window for Canadian entry into this international market. The Canadian opportunity results from three particular impacts of the new technologies: 1) the bulk of the world's uranium-enrichment capacity is in gaseous diffusion plants which, because of their large requirements for electricity (more than 2000 kW·h per SWU), are vulnerable to competition from the new processes; 2) the decline in enrichment costs increases the economic incentive for the use of slightly-enriched uranium (SEU) fuel in CANDU reactors, thus creating a potential Canadian market; and 3) the new processes allow economic operation on a much smaller scale, which drastically reduces the investment required for market entry and is comparable with the potential Canadian SEU requirement. The opportunity is not open-ended. By the end of the century the enrichment supply industry will have adapted to the new processes and long-term customer/supplier relationships will have been established. In order to seize the opportunity, Canada must become a credible supplier during this century

  14. How Diverse-CD4 Effector T Cells and their Functions

    Institute of Scientific and Technical Information of China (English)

    Yisong Y. Wan; Richard A. Flavell

    2009-01-01

    CD4 effector T cells, also called helper T (Th) cells, are the functional cells for executing immune functions. Balanced immune responses can only be achieved by proper regulation of the differentiation and function of Th cells. Dysregulated Th cell function of ten leads to inefficient clearance of pathogens and causes inflammatory diseases and autoimmunity. Since the establishment of the Th1–Th2 dogma in the 1980s, different lineages of effector T cells have been identified that not only promote but also suppress immune responses. Through years of collective efforts, much information was gained on the function and regulation of different subsets of Th cells. In this review, we attempt to sample the essence of what has been learnt in this field over the past two decades. We will discuss the classification and immunological functions of effector T cells, the determinants for effector T cell differentiation,as well as the relationship between different lineages of effector T cells.

  15. A Differential Equation Model of HIV Infection of CD4+ T-Cells with Delay

    Directory of Open Access Journals (Sweden)

    2009-02-01

    Full Text Available An epidemic model of HIV infection of CD4+ T-cells with cure rate and delay is studied. We include a baseline ODE version of the model, and a differential-delay model with a discrete time delay. The ODE model shows that the dynamics is completely determined by the basic reproduction number R0<1. If R0<1, the disease-free equilibrium is asymptotically stable and the disease dies out. If R0>1, a unique endemic equilibrium exists and is globally stable in the interior of the feasible region. In the DDE model, the delay stands for the incubation time. We prove the effect of that delay on the stability of the equilibria. We show that the introduction of a time delay in the virus-to-healthy cells transmission term can destabilize the system, and periodic solutions can arise through Hopf bifurcation.

  16. CD4+CD25+ regulatory T cells: I. Phenotype and physiology

    DEFF Research Database (Denmark)

    Holm, Thomas Lindebo; Nielsen, Janne; Claesson, Mogens H

    2004-01-01

    it has become increasingly clear that regulatory CD4+CD25+ T cells (Treg cells) play an important role in the maintenance of immunological self-tolerance, and that this cell subset exerts its function by suppressing the proliferation or function of autoreactive T cells. Based on human and murine...... observations, this review presents a characterization of the phenotype and functions of the Treg cells in vitro and in vivo. An overview of the surface molecules associated with and the cytokines produced by the Treg cells is given and the origin, activation requirements and mode of action of the Treg cells...... are discussed. Finally, we address the possibility that Treg cells may play a central role in immune homeostasis, regulating not only autoimmune responses, but also immune responses toward foreign antigens....

  17. CD4+CD25+ regulatory T cells: II. Origin, disease models and clinical aspects

    DEFF Research Database (Denmark)

    Nielsen, Janne; Holm, Thomas Lindebo; Claesson, Mogens H

    2004-01-01

    Autoimmune diseases afflict approximately 5% of the population and reflect a failure in the immune system to discriminate between self and non-self resulting in the breakdown of self-tolerance. Regulatory CD4+CD25+ T cells (Treg cells) have been shown to play an important role in the maintenance of...... immune homeostasis and self-tolerance by counteracting the development and effector functions of potentially autoreactive T cells. We have in the previous APMIS review described the phenotype and physiology of Treg cells. The present overview deals with the thymic origin of Treg cells and their role in...... disease models such as autoimmune gastritis and inflammatory bowel disease. Finally, we will consider some aspects of the therapeutic potential of Treg cells....

  18. Serine leucocyte proteinase inhibitor-treated monocyte inhibits human CD4(+) lymphocyte proliferation.

    Science.gov (United States)

    Guerrieri, Diego; Tateosian, Nancy L; Maffía, Paulo C; Reiteri, Romina M; Amiano, Nicolás O; Costa, María J; Villalonga, Ximena; Sanchez, Mercedes L; Estein, Silvia M; Garcia, Verónica E; Sallenave, Jean-Michel; Chuluyan, Héctor E

    2011-08-01

    Serine leucocyte proteinase inhibitor (SLPI) is the main serine proteinase inhibitor produced by epithelial cells and has been shown to be a pleiotropic molecule with anti-inflammatory and microbicidal activities. However, the role of SLPI on the adaptive immune response is not well established. Therefore, we evaluated the effect of SLPI on lymphocyte proliferation and cytokine production. Human peripheral blood mononuclear cells (PBMC) were treated with mitogens plus SLPI and proliferation was assessed by [(3) H]thymidine uptake. The SLPI decreased the lymphocyte proliferation induced by interleukin-2 (IL-2) or OKT3 monoclonal antibodies in a dose-dependent manner. Inhibition was not observed when depleting monocytes from the PBMC and it was restored by adding monocytes and SLPI. SLPI-treated monocyte slightly decreased MHC II and increased CD18 expression, and secreted greater amounts of IL-4, IL-6 and IL-10 in the cell culture supernatants. SLPI-treated monocyte culture supernatant inhibited the CD4(+) lymphocyte proliferation but did not affect the proliferation of CD8(+) cells. Moreover, IL-2 increased T-bet expression and the presence of SLPI significantly decreased it. Finally, SLPI-treated monocyte culture supernatant dramatically decreased interferon-γ but increased IL-4, IL-6 and IL-10 in the presence of IL-2-treated T cells. Our results demonstrate that SLPI target monocytes, which in turn inhibit CD4 lymphocyte proliferation and T helper type 1 cytokine secretion. Overall, these results suggest that SLPI is an alarm protein that modulates not only the innate immune response but also the adaptive immune response. PMID:21574992

  19. Serine leucocyte proteinase inhibitor-treated monocyte inhibits human CD4+ lymphocyte proliferation

    Science.gov (United States)

    Guerrieri, Diego; Tateosian, Nancy L; Maffía, Paulo C; Reiteri, Romina M; Amiano, Nicolás O; Costa, María J; Villalonga, Ximena; Sanchez, Mercedes L; Estein, Silvia M; Garcia, Verónica E; Sallenave, Jean-Michel; Chuluyan, Héctor E

    2011-01-01

    Serine leucocyte proteinase inhibitor (SLPI) is the main serine proteinase inhibitor produced by epithelial cells and has been shown to be a pleiotropic molecule with anti-inflammatory and microbicidal activities. However, the role of SLPI on the adaptive immune response is not well established. Therefore, we evaluated the effect of SLPI on lymphocyte proliferation and cytokine production. Human peripheral blood mononuclear cells (PBMC) were treated with mitogens plus SLPI and proliferation was assessed by [3H]thymidine uptake. The SLPI decreased the lymphocyte proliferation induced by interleukin-2 (IL-2) or OKT3 monoclonal antibodies in a dose-dependent manner. Inhibition was not observed when depleting monocytes from the PBMC and it was restored by adding monocytes and SLPI. SLPI-treated monocyte slightly decreased MHC II and increased CD18 expression, and secreted greater amounts of IL-4, IL-6 and IL-10 in the cell culture supernatants. SLPI-treated monocyte culture supernatant inhibited the CD4+ lymphocyte proliferation but did not affect the proliferation of CD8+ cells. Moreover, IL-2 increased T-bet expression and the presence of SLPI significantly decreased it. Finally, SLPI-treated monocyte culture supernatant dramatically decreased interferon-γ but increased IL-4, IL-6 and IL-10 in the presence of IL-2-treated T cells. Our results demonstrate that SLPI target monocytes, which in turn inhibit CD4 lymphocyte proliferation and T helper type 1 cytokine secretion. Overall, these results suggest that SLPI is an alarm protein that modulates not only the innate immune response but also the adaptive immune response. PMID:21574992

  20. Protein kinase C θ regulates the phenotype of murine CD4+ Th17 cells.

    Directory of Open Access Journals (Sweden)

    Katarzyna Wachowicz

    Full Text Available Protein kinase C θ (PKCθ is involved in signaling downstream of the T cell antigen receptor (TCR and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures and in vivo (experimental autoimmune encephalomyelitis model, EAE techniques, we demonstrated that PKCθ-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt, accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation.