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Sample records for cd4 enriched cervical

  1. Cervical screening in HIV-positive women in the East of England: recent CD4 as the predictive risk factor.

    Science.gov (United States)

    Davies, Olubanke; Rajamanoharan, Sasikala; Balachandran, Thambiah

    2015-11-01

    This study examines the relationship between CD4 count and cervical cytological abnormality in HIV-positive women attending two district general hospital genitourinary medicine clinics in the East of England. It aims to determine whether the rate of cervical cytological abnormalities differs in HIV-positive women with CD4 count >350 cells/µl and those with CD4 count ≤350 cells/µl; and to compare the rates of abnormalities with that of the general population. We retrospectively reviewed data from a cross-sectional audit undertaken between December 2010 and December 2011 and analysed them using multivariable statistics. There was a significant association between recent CD4 count ≤350 cells/µl and cervical cytological abnormality (p 350 cells/µl had abnormal cervical smear results, compared with 6.6% of the general population in the screening period 2010-11 and 7.2% of the general population in the screening period 2009-10. In our study population of women with recent CD4 counts >350 cells/µl, the proportions of mild, moderate and severe dysplasia were also similar to national figures. This raises important questions about the cost effectiveness of blanket annual screening for HIV-positive women.

  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. Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis

    DEFF Research Database (Denmark)

    Renno, T; Zeine, R; Girard, J M;

    1994-01-01

    The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels of expres...... stained in perivascular infiltrates in frozen sections from the brains of animals with active EAE was 10-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)...

  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

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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

  5. 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...

  6. 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

    Directory of Open Access Journals (Sweden)

    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

  7. 子宫颈上皮内瘤变患者CD4+、CD8+T细胞表达与高危型HPV感染的关系%The relationship between the expressions of CD4+ , CD8+ T cell and high risk human papillomavirus in cervical intraepithelial neoplasia

    Institute of Scientific and Technical Information of China (English)

    黎华文; 张丽帆; 冯家成

    2012-01-01

    Objective To investigate the expression of CD4+ , CD8+ T cell and hrHPV virus load in cervical intraepithelial neoplasia (CIN) and the value of HPV vaccine selection. Methods Data of 72 patients who underwent LEEP for CIN between January 2005 and August 2008 in the People's Hospital of Zhuhai were analyzed retrospectively. The expression of CD4+ , CD8+ T cell in 30 CIN1, 43 CIN2/3 and 10 normal cervical tissue specimens was determined by immunohistochemical method. hrHPV DNA virus load was detected by HC - II system. Results hrHPV-DNA virus load in normal group, CIN1 and CIN2/3 group were (6.47±12.83) pg/tnl, (187.64± 169.31) pg/ml and (312. 46±287.46) pg/ml. hrHPV - DNA virus load in CIN group was significant higher than that in normal group (P<0.01), and hrHPV - DNA virus load in CIN2/3 group was higher than in that in CIN 1 group (P<0.05). In normal group, CIN1 and CIN2/3 group, the expression rate of CD4+T cell was 60.0%, 43.3% and 33. 3%, the expression rate of CD8+ T cell was 70.0%, 46.7% and 31.0%. The expression of CD4+ and CD8+ T cell in CIN groups was significant lower than that in normal group (P<0.05). Conclusion Decreased expression of CD4+ , CD8+ T cell may result in high hrHPV - DNA virus persistence and thus enhance cervical cancerous.%目的 探讨不同级别宫颈上皮内瘤变(CIN)组织中CD4+、CD8+T细胞表达及与高危型人乳头瘤病毒(HR-HPV)的关系.方法 对2005年1月至2008年8月在珠海市人民医院阴道镜下宫颈活检诊断为CIN并行宫颈锥切治疗的72例患者的资料进行分析,采用杂交捕获第二代方法(HC-Ⅱ)检测高危型HPVDNA含量;采用免疫组化检测30例CIN1、43例CIN2/3及10例正常宫颈组织中CD4+、CD8+T细胞的表达.结果 CIN2/3组的HR-HPV感染率显著高于CIN1组(P<0.05),CIN组HR-HPV感染率高于慢性宫颈炎组(P<0.01).慢性宫颈炎组、CIN1组和CIN 2/3组CD4+T细胞表达率分别为60.0%、43.3%和33.3%,CD8+T细胞的表达率分别为70.0

  8. HuMax-CD4

    DEFF Research Database (Denmark)

    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.

    Science.gov (United States)

    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. 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...

  12. CD4-regulatory cells in COPD patients

    DEFF Research Database (Denmark)

    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. 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......-negative donors. CD4 cells from HIV-positive patients were readily expanded with PHA; 19-fold by day 10, 50-fold by day 20, and 156-fold by day 25. However, CD4 cells from HIV-positive patients grew at a slower rate than CD4 cells from HIV-negative donors. The expanded CD4 cells showed a high degree of CD4...

  14. 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.

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

    Science.gov (United States)

    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. 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.

  17. Idiopathic CD4 lymphocytopenia with sensorimotor polyneuropathy.

    Science.gov (United States)

    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

  18. Idiopathic CD4 lymphocytopenia with sensorimotor polyneuropathy

    Directory of Open Access Journals (Sweden)

    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.

  19. 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.

  20. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo.

    Science.gov (United States)

    Simonetti, Francesco R; Sobolewski, Michele D; Fyne, Elizabeth; Shao, Wei; Spindler, Jonathan; Hattori, Junko; Anderson, Elizabeth M; Watters, Sarah A; Hill, Shawn; Wu, Xiaolin; Wells, David; Su, Li; Luke, Brian T; Halvas, Elias K; Besson, Guillaume; Penrose, Kerri J; Yang, Zhiming; Kwan, Richard W; Van Waes, Carter; Uldrick, Thomas; Citrin, Deborah E; Kovacs, Joseph; Polis, Michael A; Rehm, Catherine A; Gorelick, Robert; Piatak, Michael; Keele, Brandon F; Kearney, Mary F; Coffin, John M; Hughes, Stephen H; Mellors, John W; Maldarelli, Frank

    2016-02-16

    Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4(+)T cells. Some of these CD4(+)T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4(+) T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1-infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4(+)T cells can be a reservoir of infectious HIV-1.

  1. 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...

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

    OpenAIRE

    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...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    CD4(+)/CD8(+) DP thymocytes are a well-described T cell developmental stage within the thymus. However, once differentiated, the CD4(+) lineage or the CD8(+) lineage is generally considered to be fixed. Nevertheless, mature CD4(+)/CD8(+) DP T cells have been described in the blood and peripheral...... cells, CD4(+)/CD8(+) T cell populations, outside of the thymus, have recently been described to express concurrently ThPOK and Runx3. Considerable heterogeneity exists within the CD4(+)/CD8(+) DP T cell pool, and the function of CD4(+)/CD8(+) T cell populations remains controversial, with conflicting...... reports describing cytotoxic or suppressive roles for these cells. In this review, we describe how transcriptional regulation, lineage of origin, heterogeneity of CD4 and CD8 expression, age, species, and specific disease settings influence the functionality of this rarely studied T cell population....

  6. 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

  7. CRTAM determines the CD4+ cytotoxic T lymphocyte lineage.

    Science.gov (United States)

    Takeuchi, Arata; Badr, Mohamed El Sherif Gadelhaq; Miyauchi, Kosuke; Ishihara, Chitose; Onishi, Reiko; Guo, Zijin; Sasaki, Yoshiteru; Ike, Hiroshi; Takumi, Akiko; Tsuji, Noriko M; Murakami, Yoshinori; Katakai, Tomoya; Kubo, Masato; Saito, Takashi

    2016-01-11

    Naive T cells differentiate into various effector T cells, including CD4(+) helper T cell subsets and CD8(+) cytotoxic T cells (CTL). Although cytotoxic CD4(+) T cells (CD4 +: CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4(+) T cells that express class I-restricted T cell-associated molecule (CRTAM) upon activation possesses the characteristics of both CD4(+) and CD8(+) T cells. CRTAM(+) CD4(+) T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM(+) T cells are the precursor of CD4(+)CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4(+)CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM(+) T cells traffic to mucosal tissues and inflammatory sites and developed into CD4(+)CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4(+)CTL through the induction of Eomes and CTL-related gene.

  8. 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.

  9. Monoclonal Anti—CD4 Antibody MT310 Binds HIV-1 gp120 Binding Site on CD4

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Tests show the monoclonal anti—CD4 antibody (mAb) MT310 recognizes the gp120-binding site on CD4 as part of its mechanism for strongly inhibiting human immunodeficiency virus type 1 (HIV-1) infection of CD4+ T cells. In competition tests, mAb MT310 and mAb Leu3a (an anti-CD4 mAb recognizing the gp120-binding site) all inhibited gp120-binding to CD4+ T lymphocytes, while mAb MT405 did not. This result suggests that MT310, like Leu3a, recognizes the gp120-binding site on CD4. To further confirm whether MT310 recognizes the gp120-binding site on CD4, we prepared rabbit anti-idiotypic antisera (Ab2) against MT310 (Ab1). The anti-idiotypic antisera against MT310 inhibited binding of MT310 and Leu3a to human CD4+ T lymphocytes, but did not block binding of MT151 with the second domain of CD4, while rabbit anti-idiotypic antisera to MT151 could block binding of itself to these cells, but could not inhibit the binding of MT310 and Leu3a, further indicating that MT310 recognized the gp120-binding site on CD4.

  10. 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

  11. An increased frequency of autoantibody-inducing CD4+ T cells in pre-diseased lupus-prone mice.

    Science.gov (United States)

    Busser, Brian W; Cancro, Michael P; Laufer, Terri M

    2004-07-01

    Pathogenic autoantibody production in murine models of lupus is dependent on autoreactive CD4+ helper T cells. However, the mechanisms which permit the selection and maintenance of this autoantibody-inducing CD4+ T-cell repertoire are currently unknown. We hypothesized that the peripheral CD4+ T-cell repertoire of lupus-prone mice was enriched with autoantibody-inducing specificities. To test this, we utilized the splenic focus assay to determine if pre-diseased lupus-prone (NZB x NZW)F(1) mice have an elevated frequency of autoreactive CD4+ T lymphocytes capable of supporting autoantibody production. The splenic focus limiting dilution assay permits anti-nuclear antibodies to be generated from contact-dependent T-B interactions in vitro. We show that young, pre-diseased lupus-prone mice have an elevated frequency of autoantibody-inducing CD4+ T cells. Interestingly, these autoantibody-inducing CD4+ T-cell responses are also present in the thymus. Therefore, an elevated frequency of autoantibody-inducing CD4+ T cells predisposes lupus-prone mice to the development of autoantibodies.

  12. 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.

  13. Thymic Nurse Cells Support CD4-CD8+ Thymocytes to Differentiate into CD4+CD8+ Cells

    Institute of Scientific and Technical Information of China (English)

    Aidong Li; Xueli Liu; Baochun Duan; Jie Ma

    2005-01-01

    Thymic nurse cells (TNCs) represent a unique microenvironment in the thymus for T cell maturation. In order to investigate the role of thymic nurse cells during T cell differentiation, a TNC clone, RWTE-1, which formed a typical complex with fetal thymocytes in vitro was established from normal Wistar rat. Hanging drop culture method was applied to reveal the interaction between TNCs and thymocytes. Our result revealed that eighty percent of immature CD4-CD8+ cells differentiated into CD4+CD8+ cells after a 12-hour hanging drop culture with RWTE-1. However, in a 12-hour culture of immature CD4-CD8+ cells with or without RWTE-1 supernatant, only 30% of the cells differentiated into CD4+CD8+ cells spontaneously. This observation led to the conclusion that RWTE-1 cell has the capacity to facilitate immature CD4-CD8+ thymocytes to differentiate into CD4+CD8+ T cells by direct interaction.

  14. Sialylation regulates peripheral tolerance in CD4+ T cells.

    Science.gov (United States)

    Brennan, Patrick J; Saouaf, Sandra J; Van Dyken, Steve; Marth, Jamey D; Li, Bin; Bhandoola, Avinash; Greene, Mark I

    2006-05-01

    Decreased binding by the 6C10 auto-antibody serves as a unique marker for CD4+ T cell unresponsiveness after the induction of T cell tolerance in Vbeta8.1 TCR transgenic mice. We further define the nature of the epitope recognized by the 6C10 antibody to be a subset of Thy-1 bearing incompletely sialylated N-linked glycans, and furthermore, we demonstrate that tolerant CD4+ T cells have an increased degree of cell-surface sialylation. To test the significance of the altered glycosylation state identified by the 6C10 auto-antibody in the tolerant CD4+ T cell population, surface sialic acid was cleaved enzymatically. Treatment of purified peripheral CD4+ T cells with Vibrio cholerae sialidase (VCS) leads to increased 6C10 binding, significantly enhances proliferation in the tolerant CD4+ population and corrects defects in phosphotyrosine signaling observed in the tolerant CD4+ T cell. Furthermore, in vivo administration of VCS enhances proliferation in both tolerant and naive CD4+ T cell subsets. These studies suggest that sialylation of glycoproteins on the surface of the CD4+ T cell contributes to the regulation of T cell responsiveness in the tolerant state. PMID:16291658

  15. CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART

    Science.gov (United States)

    Fromentin, Rémi; Bakeman, Wendy; Lawani, Mariam B.; Khoury, Gabriela; Hartogensis, Wendy; DaFonseca, Sandrina; Killian, Marisela; Epling, Lorrie; Hoh, Rebecca; Sinclair, Elizabeth; Hecht, Frederick M.; Bacchetti, Peter; Deeks, Steven G.; Lewin, Sharon R.; Sékaly, Rafick-Pierre; Chomont, Nicolas

    2016-01-01

    HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals. PMID:27415008

  16. 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

  17. 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

  18. CD4~+CD56~+ hematodermic neoplasm in a child

    Institute of Scientific and Technical Information of China (English)

    GUO Xia; LI Qiang; ZHOU Chen-yan

    2010-01-01

    @@ CD4~+CD56~+ hematodermic neoplasm (HN) is a rare, highly aggressive systemic neoplasm, which had been described under various names including lymphoblastic lymphoma of natural killer (NK) phenotype, blastic NK cell lymphoma (BNK), leukemic lymphoma of immature NK lineage and CD4~+CD56~+ HN. This malignancy is mainly involved in elderly people and usually a rapidly fatal disease, since consistently effective treatments have not yet been developed. It is relatively rare in children.~(1-6) Herein we report a boy with CD4~+CD56~+ HN.

  19. 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 ...

  20. Evaluation of the impact of chitosan/DNA nanoparticles on the differentiation of human naive CD4{sup +} T cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu Lanxia; Bai Yuanyuan; Zhu Dunwan; Song Liping; Wang Hai; Dong Xia; Zhang Hailing; Leng Xigang, E-mail: lengxg@bme.org.cn [Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin Key Laboratory of Biomedical Materials, Lab of Bioengineering, Institute of Biomedical Engineering (China)

    2011-06-15

    Chitosan (CS) is one of the most widely studied polymers in non-viral gene delivery since it is a cationic polysaccharide that forms nanoparticles with DNA and hence protects the DNA against digestion by DNase. However, the impact of CS/DNA nanoparticle on the immune system still remains poorly understood. Previous investigations did not found CS/DNA nanoparticles had any significant impact on the function of human and murine macrophages. To date, little is known about the interaction between CS/DNA nanoparticles and naive CD4{sup +} T cells. This study was designed to investigate whether CS/DNA nanoparticles affect the initial differentiation direction of human naive CD4{sup +} T cells. The indirect impact of CS/DNA nanoparticles on naive CD4{sup +} T cell differentiation was investigated by incubating the nanoparticles with human macrophage THP-1 cells in one chamber of a transwell co-incubation system, with the enriched human naive CD4{sup +} T cells being placed in the other chamber of the transwell. The nanoparticles were also co-incubated with the naive CD4{sup +} T cells to explore their direct impact on naive CD4{sup +} T cell differentiation by measuring the release of IL-4 and IFN-{gamma} from the cells. It was demonstrated that CS/DNA nanoparticles induced slightly elevated production of IL-12 by THP-1 cells, possibly owing to the presence of CpG motifs in the plasmid. However, this macrophage stimulating activity was much less significant as compared with lipopolysaccharide and did not impact on the differentiation of the naive CD4{sup +} T cells. It was also demonstrated that, when directly exposed to the naive CD4{sup +} T cells, the nanoparticles induced neither the activation of the naive CD4{sup +} T cells in the absence of recombinant cytokines (recombinant human IL-4 or IFN-{gamma}) that induce naive CD4{sup +} T cell polarization, nor any changes in the differentiation direction of naive CD4{sup +} T cells in the presence of the corresponding

  1. Cyclotriazadisulfonamides: promising new CD4-targeted anti-HIV drugs.

    Science.gov (United States)

    Vermeire, Kurt; Schols, Dominique

    2005-08-01

    It is imperative to continue efforts to identify novel effective therapies that can assist in containing the spread of HIV. Recently acquired knowledge about the HIV entry process points to new strategies to block viral entry. For most HIV strains, the successful infection of their target cells is mainly dependent on the presence of the CD4 surface molecule, which serves as the primary virus receptor. The attachment of the viral envelope to this cellular CD4 receptor can be considered as an ideal target with multiple windows of opportunity for therapeutic intervention. Therefore, drugs that interfere with the CD4 receptor, and thus inhibit viral entry, may be promising agents for the treatment of AIDS. The CD4-targeted HIV entry inhibitors cyclotriazadisulfonamides represent a novel class of small molecule antiviral agents with a unique mode of action. The lead compound, CADA, specifically interacts with the cellular CD4 receptor and is active against a wide variety of HIV strains at submicromolar levels when evaluated in different cell-types such as T cells, monocytes and dendritic cells. Moreover, a strict correlation has been demonstrated between anti-HIV activity and CD4 interaction of about 20 different CADA analogues. In addition, CADA acted synergistically in combination with all other FDA-approved anti-HIV drugs as well as with compounds that target the main HIV co-receptors. In this article, the characteristics of cyclotriazadisulfonamide compounds are presented and the possible application of CADA as a microbicide is also discussed. PMID:15980096

  2. 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...

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

    Directory of Open Access Journals (Sweden)

    Charlotte eMariani

    2014-06-01

    Full Text Available HIV-1 is an RNA enveloped virus that preferentiallyinfects CD4+ T lymphocytes andalso macrophages. In CD4+ T cells, HIV-1mainly buds from the host cell plasma membrane.The viral Gag polyprotein targets theplasma membrane and is the orchestrator ofthe HIV assembly as its expression is sufficientto promote the formation of virus-likeparticles particles carrying a lipidic envelopederiving from the host cell membrane. Certainlipids are enriched in the viral membraneand are thought to play a key role in theassembly process and the envelop composition.A large body of work performed oninfected CD4+ T cells has provided importantknowledge about the assembly process andthe membrane virus lipid composition. WhileHIV assembly and budding in macrophages isthought to follow the same general Gag-drivenmechanism as in T-lymphocytes, the HIV cyclein macrophage exhibits specific features.In these cells, new virions bud from the limitingmembrane of seemingly intracellular compartments,where they accumulate while remaininginfectious. These structures are now oftenreferred to as Virus Containing Compartments(VCCs. Recent studies suggest that VCCsrepresent intracellularly sequestered regionsof the plasma membrane, but their precisenature remains elusive. The proteomic andlipidomic characterization of virions producedby T cells or macrophages has highlightedthe similarity between their composition andthat of the plasma membrane of producercells, as well as their enrichment in acidiclipids, some components of raft lipids andin tetraspanin-enriched microdomains. Greatchances are that Gag promotes the coalescenceof these components into an assemblyplatform from which viral budding takesplace. How Gag exactly interacts with membranelipids and what are the mechanisms involvedin the interaction between the differentmembrane nanodomains within the assemblyplatform remains unclear. Here we review recentliterature regarding the role of Gag andlipids

  4. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

    Science.gov (United States)

    Falloon, Judith; Bennett, John E.; Shaw, Pamela A.; Chaitt, Doreen; Baseler, Michael W.; Adelsberger, Joseph W.; Metcalf, Julia A.; Polis, Michael A.; Kovacs, Stephen J.; Kovacs, Joseph A.; Davey, Richard T.; Lane, H. Clifford; Masur, Henry

    2008-01-01

    Idiopathic CD4+ lymphocytopenia (ICL) is a rare non–HIV-related syndrome with unclear natural history and prognosis. This prospective natural history cohort study describes the clinical course, CD4 T lymphocyte kinetics, outcome, and prognostic factors of ICL. Thirty-nine patients (17 men, 22 women) 25 to 85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections. Seven patients presented with no infection. In 32, CD4 T-cell counts remained less than 300/mm3 throughout the study period and in 7 normalized after an average of 31 months. Overall, 15 (41.6%) developed an opportunistic infection in follow-up, 5 (13.8%) of which were “AIDS-defining clinical conditions,” and 4 (11.1%) developed autoimmune diseases. Seven patients died, 4 from ICL-related opportunistic infections, within 42 months after diagnosis. Immunologic analyses revealed increased activation and turnover in CD4 but not CD8 T lymphocytes. CD8 T lymphocytopenia (< 180/mm3) and the degree of CD4 T cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death; P = .003 and .02, respectively). This trial is registered at http://clinicaltrials.gov as #NCT00001319. PMID:18456875

  5. 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

  6. 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.

  7. 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

  8. Transcriptional regulatory networks for CD4 T cell differentiation.

    Science.gov (United States)

    Christie, Darah; Zhu, Jinfang

    2014-01-01

    CD4(+) T cells play a central role in controlling the adaptive immune response by secreting cytokines to activate target cells. Naïve CD4(+) T cells differentiate into at least four subsets, Th1Th1 , Th2Th2 , Th17Th17 , and inducible regulatory T cellsregulatory T cells , each with unique functions for pathogen elimination. The differentiation of these subsets is induced in response to cytokine stimulation, which is translated into Stat activation, followed by induction of master regulator transcription factorstranscription factors . In addition to these factors, multiple other transcription factors, both subset specific and shared, are also involved in promoting subset differentiation. This review will focus on the network of transcription factors that control CD4(+) T cell differentiation.

  9. HIV-1 induces DCIR expression in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Alexandra A Lambert

    Full Text Available The C-type lectin receptor DCIR, which has been shown very recently to act as an attachment factor for HIV-1 in dendritic cells, is expressed predominantly on antigen-presenting cells. However, this concept was recently challenged by the discovery that DCIR can also be detected in CD4(+ T cells found in the synovial tissue from rheumatoid arthritis (RA patients. Given that RA and HIV-1 infections share common features such as a chronic inflammatory condition and polyclonal immune hyperactivation status, we hypothesized that HIV-1 could promote DCIR expression in CD4(+ T cells. We report here that HIV-1 drives DCIR expression in human primary CD4(+ T cells isolated from patients (from both aviremic/treated and viremic/treatment naive persons and cells acutely infected in vitro (seen in both virus-infected and uninfected cells. Soluble factors produced by virus-infected cells are responsible for the noticed DCIR up-regulation on uninfected cells. Infection studies with Vpr- or Nef-deleted viruses revealed that these two viral genes are not contributing to the mechanism of DCIR induction that is seen following acute infection of CD4(+ T cells with HIV-1. Moreover, we report that DCIR is linked to caspase-dependent (induced by a mitochondria-mediated generation of free radicals and -independent intrinsic apoptotic pathways (involving the death effector AIF. Finally, we demonstrate that the higher surface expression of DCIR in CD4(+ T cells is accompanied by an enhancement of virus attachment/entry, replication and transfer. This study shows for the first time that HIV-1 induces DCIR membrane expression in CD4(+ T cells, a process that might promote virus dissemination throughout the infected organism.

  10. 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...

  11. 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.

  12. 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.

  13. 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. ...

  14. Advanced glycation end products promote differentiation of CD4(+) T helper cells toward pro-inflammatory response.

    Science.gov (United States)

    Han, Xiao-qun; Gong, Zuo-jiong; Xu, San-qing; Li, Xun; Wang, Li-kun; Wu, Shi-min; Wu, Jian-hong; Yang, Hua-fen

    2014-02-01

    This study investigated the effect of advanced glycation end products (AGEs) on differentiation of naïve CD4(+) T cells and the role of the receptor of AGEs (RAGE) and peroxisome proliferator-activated receptors (PPARs) activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin (BSA) with glucose. Human naïve CD4(+) T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin (sh) RNA knock-down experiment, naïve CD4(+) T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-X(TM) 293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4(+) T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T (Treg) cells was determined by a [(3)H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from naïve CD4(+) T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in naïve CD4(+) T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4(+) T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα PPARγ agonist, PGJ2, inhibited the effect of AGEs on naïve CD4(+) T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It

  15. 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

  16. Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

    DEFF Research Database (Denmark)

    Kristiansen, O P; Karlsen, A E; Larsen, Z M;

    2004-01-01

    CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we ...

  17. 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.

  18. 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...

  19. 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...

  20. 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.

  1. Early Postseroconversion CD4 Cell Counts Independently Predict CD4 Cell Count Recovery in HIV-1–Postive Subjects Receiving Antiretroviral Therapy

    Science.gov (United States)

    Kulkarni, Hemant; Okulicz, Jason F.; Grandits, Greg; Crum-Cianflone, Nancy F.; Landrum, Michael L.; Hale, Braden; Wortmann, Glenn; Tramont, Edmund; Polis, Michael; Dolan, Matthew; Lifson, Alan R.; Agan, Brian K.; Ahuja, Sunil K.; Marconi, Vincent C.

    2013-01-01

    Background The relationship between CD4+ T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown. Methods Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4+ T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well-characterized cohort. The association of baseline with post-HAART CD4+ T-cell count was determined after adjustment for other relevant covariates. Results A higher baseline CD4+ T-cell count predicted a greater post- HAART CD4+ T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4+ count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/baseline count ratio was consistently ≥0.6. Conclusions Among viral load suppressing seroconverters, the absolute CD4+ T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4+ T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons. PMID:21546844

  2. CD4 Variability in Malawi: Implications for Use of a CD4 Threshold of 500 Cells/mm3 Versus Universal Eligibility for Antiretroviral Therapy

    Science.gov (United States)

    Schooley, Alan L.; Kamudumuli, Pocha Samuel; Vangala, Sitaram; Tseng, Chi-hong; Soko, Chifundo; Parent, Julie; Phiri, Khumbo; Jahn, Andreas; Namarika, Dan; Hoffman, Risa M.

    2016-01-01

    Background. Given the uncertainty about the ability of a single CD4 count to accurately classify a patient as antiretroviral therapy (ART) eligible, we sought to understand the extent to which CD4 variability results in misclassification at a CD4 threshold of 500 cells/mm3. Methods. We performed a prospective study of CD4 variability in Malawian human immunodeficiency virus-infected, ART-naive, World Health Organization (WHO) stage 1 or 2, nonpregnant adults. CD4 counts were performed daily for 8 days. We fit a Bayesian linear mixed-effects model of log-transformed CD4 cell counts to the data. We used Monte Carlo approximations to estimate misclassification rates for different observed values of CD4. The misclassification rate was calculated based on the conditional probability of true CD4 given the geometric mean of observed CD4 measurements. Results. Fifty patients were enrolled from 2 sites. The median age was 33.5 years (interquartile range, 27.5–40.0) and 34 (68%) were female. Misclassification rates were <1% when the observed CD4 counts were ≤250 or ≥750 cells/mm3. Rates of misclassification were high at observed CD4 counts between 350 and 650 cells/mm3, particularly when a single measurement was used (up to 46.7%). Conclusions. Our data show that ART eligibility based on a single CD4 count results in highest risk of misclassification when observed CD4 counts are in the range of 350–650 cells/mm3. Given the benefits of early ART, countries should weigh the costs and complexity of CD4 testing using a 500 cell/mm3 threshold against the cost savings and public health benefits of universal eligibility. PMID:27704028

  3. 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.

  4. 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.

  5. Docosahexaenoic acid reduces suppressive and migratory functions of CD4CD25 regulatory T-cells

    Science.gov (United States)

    Yessoufou, Akadiri; Plé, Aude; Moutairou, Kabirou; Hichami, Aziz; Khan, Naim Akhtar

    2009-01-01

    Immunological tolerance is one of the fundamental aspects of the immune system. The CD4+CD25+ regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4+CD25− effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-β, and IL-10; nonetheless, this fatty acid increased the expression of p27KIP1 mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease. PMID:19561360

  6. 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.

  7. 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.

  8. Memory T follicular helper CD4 T cells

    Directory of Open Access Journals (Sweden)

    J. Scott eHale

    2015-02-01

    Full Text Available T follicular helper (Tfh cells are the subset of CD4 T helper cells that are required for generation and maintenance of germinal center reactions and the generation of long-lived humoral immunity. This specialized T helper subset provides help to cognate B cells via their expression of CD40 ligand, IL-21, IL-4, and other molecules. Tfh cells are characterized by their expression of the chemokine receptor CXCR5, expression of the transcriptional repressor Bcl6, and their capacity to migrate to the follicle and promote germinal center B cell responses. Until recently, it remained unclear whether Tfh cells differentiated into memory cells and whether they maintain their Tfh commitment at the memory phase. This review will highlight several recent studies that support the idea of Tfh-committed CD4 T cells at the memory stage of the immune response. The implication of these findings is that memory Tfh cells retain their capacity to recall their Tfh-specific effector functions upon reactivation to provide help for B cell responses and play an important role in prime and boost vaccination or during recall responses to infection. The markers that are useful for distinguishing Tfh effector and memory cells, as well as the limitations of using these markers will be discussed. Tfh effector and memory generation, lineage maintenance, and plasticity relative to other T helper lineages (Th1, Th2, Th17, etc will also be discussed. Ongoing discoveries regarding the maintenance and lineage stability versus plasticity of memory Tfh cells will improve strategies that utilize CD4 T cell memory to modulate antibody responses during prime and boost vaccination.

  9. 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...

  10. 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...

  11. 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...

  12. 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

  13. CD4+ T Lymphocytes are Not Necessary for the Acute Rejection of Vascularized Mouse Lung Transplants

    OpenAIRE

    Gelman, Andrew E.; Okazaki, Mikio; Lai, Jiaming; Kornfeld, Christopher G.; Kreisel, Friederike H.; Richardson, Steven B.; Sugimoto, Seiichiro; Tietjens, Jeremy R.; Patterson, G. Alexander; Krupnick, Alexander S.; Kreisel, Daniel

    2008-01-01

    Acute rejection continues to present a major obstacle to successful lung transplantation. While CD4+ T lymphocytes are critical for the rejection of some solid organ grafts the role of CD4+ T cells in the rejection of lung allografts is largely unknown. In this study we demonstrate in a novel model of orthotopic vascularized mouse lung transplantation that acute rejection of lung allografts is independent of CD4+ T cell-mediated allorecognition pathways. CD4+ T cell-independent rejection occu...

  14. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies

    Science.gov (United States)

    Zarling, Joyce M.; Moran, Patricia A.; Haffar, Omar; Sias, Joan; Richman, Douglas D.; Spina, Celsa A.; Myers, Dorothea E.; Kuebelbeck, Virginia; Ledbetter, Jeffrey A.; Uckun, Fatih M.

    1990-09-01

    FUNCTIONAL impairment and selective depletion of CD4+ T cells, the hallmark of AIDS, are at least partly caused by human immunodeficiency virus (HIV-1) type 1 binding to the CD4 molecule and infecting CD4+ cells1,2. It may, therefore, be of therapeutic value to target an antiviral agent to CD4+ cells to prevent infection and to inhibit HIV-1 production in patients' CD4+ cells which contain proviral DNA3,4. We report here that HIV-1 replication in normal primary CD4+ T cells can be inhibited by pokeweed antiviral protein, a plant protein of relative molecular mass 30,000 (ref. 5), which inhibits replication of certain plant RNA viruses6-8, and of herpes simplex virus, poliovirus and influenza virus9-11. Targeting pokeweed antiviral protein to CD4+ T cells by conjugating it to monoclonal antibodies reactive with CDS, CD7 or CD4 expressed on CD4+ cells, increased its anti-HIV potency up to 1,000-fold. HIV-1 replication is inhibited at picomolar concentrations of conjugates of pokeweed antiviral protein and monoclonal antibodies, which do not inhibit proliferation of normal CD4+ T cells or CD4-dependent responses. These conjugates inhibit HIV-1 protein synthesis and also strongly inhibit HIV-1 production in activated CD4+ T cells from infected patients.

  15. 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.

  16. 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

  17. 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, splee...

  18. CD4+CD25hiFOXP3+ cells in cord blood of neonates born from filaria infected mother are negatively associated with CD4+Tbet+ and CD4+RORγt+ T cells.

    Directory of Open Access Journals (Sweden)

    Ulysse Ateba-Ngoa

    Full Text Available BACKGROUND: Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses. METHODOLOGY: Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3. RESULTS: No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = -0.242, P = 0.002; B = -0.178, P = 0.013 respectively. CONCLUSION: Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check.

  19. 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.

  20. Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults.

    Science.gov (United States)

    Leddon, Scott A; Richards, Katherine A; Treanor, John J; Sant, Andrea J

    2015-09-01

    CD4 T-cell responses are functionally complex and regulate many aspects of innate and adaptive immunity. Follicular helper (Tfh) cells are CD4 T cells specialized to support B-cell production of isotype-switched, high-affinity antibody. So far, studies of Tfh cells in humans have focused on their differentiation requirements, with little research devoted to their antigen specificity. Here, after separating circulating human memory CD4 T cells based on expression of CXCR5, a signature marker of Tfh, we have quantified and assayed the influenza protein antigen specificity of blood Tfh cells and CD4 T cells lacking this marker. Through the use of peptide pools derived from nucleoprotein (NP) or haemagglutinin (HA) and a panel of human donors, we have discovered that circulating Tfh cells preferentially recognize peptide epitopes from HA while cells lacking CXCR5 are enriched for specificity toward NP. These studies suggest that reactive CD4 T cells specific for distinct viral antigens may have generalized differences in their functional potential due to their previous stimulation history. PMID:26094691

  1. 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

  2. CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.

    Directory of Open Access Journals (Sweden)

    Andreas Schweizer

    2008-07-01

    Full Text Available Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin technology. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. These 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C HIV isolates in the low nanomolar range, independent of coreceptor usage. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins-high physical stability, specificity and low production costs-with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development.

  3. DC-SIGN increases the affinity of HIV-1 envelope glycoprotein interaction with CD4.

    Directory of Open Access Journals (Sweden)

    Karolin Hijazi

    Full Text Available Mannose-binding C-type lectin receptors, expressed on Langerhans cells and subepithelial dendritic cells (DCs of cervico-vaginal tissues, play an important role in HIV-1 capture and subsequent dissemination to lymph nodes. DC-SIGN has been implicated in both productive infection of DCs and the DC-mediated trans infection of CD4(+ T cells that occurs in the absence of replication. However, the molecular events that underlie this efficient transmission have not been fully defined. In this study, we have examined the effect of the extracellular domains of DC-SIGN and Langerin on the stability of the interaction of the HIV-1 envelope glycoprotein with CD4 and also on replication in permissive cells. Surface plasmon resonance analysis showed that DC-SIGN increases the binding affinity of trimeric gp140 envelope glycoproteins to CD4. In contrast, Langerin had no effect on the stability of the gp140:CD4 complex. In vitro infection experiments to compare DC-SIGN enhancement of CD4-dependent and CD4-independent strains demonstrated significantly lower enhancement of the CD4-independent strain. In addition DC-SIGN increased the relative rate of infection of the CD4-dependent strain but had no effect on the CD4-independent strain. DC-SIGN binding to the HIV envelope protein effectively increases exposure of the CD4 binding site, which in turn contributes to enhancement of infection.

  4. [The Analysis for Probable Reasons of Cd4+ T-Cell Activation Non-Linear Dependence on Extra Cellular Calcium Ion Concentration in Human Peripheral Blood in vitro].

    Science.gov (United States)

    Litvinov, I S

    2015-01-01

    The analysis for probable reasons of CD4+ T-cell activation non-linear dependence on [Ca2+]o in HPB in vitro is the general aim of current work. At the beginning we pursued the analysis of receptor-dependent (the mixture of monoclonal antibodies (mAbs) to CD3 and CD28 molecules) and receptor-independent (phorbol-myristate-acetate and ionomycin mixture) means to activate T cells in vitro with different [Ca2+]o in HPB. The key role of intracellular T-cell signaling systems in activated T cells in their non-similar sensitivity to calcium ions in the blood was shown. The analysis of differentiation next stages of CD4+ T-cell activation in vitro relatively [Ca2+]o in PHB demonstrates the key role of the earliest induction stages in non-similar sensitivity to calcium ions in CD4+ T-cell activation in vitro. According to the pursued analysis; the non-similar sensitivity of CD4+ T-cell in vitro to activation is in no-way connected with pace differences on the primary stages of activation process. The comparison of CD4+ memory T cells with their naive T-cell precursors in the cell activation process in hypocalcemia conditions was made in the separate experimental series. The 1st maximum consists in average of 85% CD4+CD45R0high CD69+ memory T cells. Naive CD4+CD45RAlowCD69+ T cells constitute the remainder 15%. The 2nd maximum almost completely consists of CD4+CD45R0+CD69+ memory T cells. The ratio between CD4+CD69+ T cell maximums depends on donor ages and represents linear dependence with R = -0.981. The most probable candidate on the role of CD4+ T cell, being capable of activation in hypocalcemia conditions, are memory T lymphocytes, being resistant to ionomycin action (I R) subset. To check this assumption the mononuclear cells and their IR-fraction were prepared from donor PB. Then the mononuclear cells and their IR-fraction were activated by mAbs mixture at different [EGTA] values. For IR-fraction, enriched with CD4+CD45RA-CD45R0+ memory T cells, slightly seen 1st

  5. 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.

  6. 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...

  7. 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. ...

  8. 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....

  9. NAD+ protects against EAE by regulating CD4+ T-cell differentiation

    Science.gov (United States)

    Tullius, Stefan G.; Biefer, Hector Rodriguez Cetina; Li, Suyan; Trachtenberg, Alexander J.; Edtinger, Karoline; Quante, Markus; Krenzien, Felix; Uehara, Hirofumi; Yang, Xiaoyong; Kissick, Haydn T.; Kuo, Winston P.; Ghiran, Ionita; de la Fuente, Miguel A.; Arredouani, Mohamed S.; Camacho, Virginia; Tigges, John C.; Toxavidis, Vasilis; El Fatimy, Rachid; Smith, Brian D.; Vasudevan, Anju; ElKhal, Abdallah

    2014-01-01

    CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases. PMID:25290058

  10. Blocking of HIV-1 Infectivity by a Soluble, Secreted Form of the CD4 Antigen

    Science.gov (United States)

    Smith, Douglas H.; Byrn, Randal A.; Marsters, Scot A.; Gregory, Timothy; Groopman, Jerome E.; Capon, Daniel J.

    1987-12-01

    The initial event in the infection of human T lymphocytes, macrophages, and other cells by human immunodeficiency virus (HIV-1) is the attachment of the HIV-1 envelope glycoprotein gp120 to its cellular receptor, CD4. As a step toward designing antagonists of this binding event, soluble, secreted forms of CD4 were produced by transfection of mammalian cells with vectors encoding versions of CD4 lacking its transmembrane and cytoplasmic domains. The soluble CD4 so produced binds gp120 with an affinity and specificity comparable to intact CD4 and is capable of neutralizing the infectivity of HIV-1. These studies reveal that the high-affinity CD4-gp120 interaction does not require other cell or viral components and may establish a novel basis for therapeutic intervention in the acquired immune deficiency syndrome (AIDS).

  11. Lack of permissivity of human monoclonal CD4+ lymphocytes to HIV.

    Science.gov (United States)

    Chapel, A; Bourges, J F; Bensussan, A; d'Auriol, L; Vilmer, E; Dormont, D

    1990-01-01

    Although knowledge has accumulated about GP110-CD4 interaction, viral penetration into human CD4+ lymphocytes remains unclear, in spite of the fact that all studies on HIV infection were performed on cell-transformed lineages, or on human polyclonal CD4+ cells. In order to investigate this viral entrance into susceptible cells, we studied the permissivity of 13 human monoclonal CD4+ lymphocytes by means of reverse transcriptase (RT) assay and immunocapture. We demonstrated a differential susceptibility to HIV of these CD4+ clones. In a second experiment, HIV infection was studied: (1) sequentially by RT assay and P24 immunocapture on several clones; (2) by cocultivation of infected clones with umbilical cord lymphocytes. These experiments suggested existence of permissive and "nonpermissive" CD4+ monoclonal lymphocytes. Slot blot, then PCR, revealed that proviral DNA sequences were detectable in all clones, but were present at lower levels in nonpermissive clones.

  12. Enteroantigen-presenting B cells efficiently stimulate CD4(+) T cells in vitro

    DEFF Research Database (Denmark)

    Schmidt, Esben Gjerløff Wedebye; Kristensen, Nanna Ny; Claesson, Mogens Helweg;

    2011-01-01

    Presentation of enterobacterial antigens by antigen-presenting cells and activation of enteroantigen-specific CD4(+) T cells are considered crucial steps in inflammatory bowel disease (IBD) pathology. The detrimental effects of such CD4(+) T cells have been thoroughly demonstrated in models...... of colitis. Also, we have previously established an in vitro assay where murine enteroantigen-specific colitogenic CD4(+) CD25(-) T cells are activated by splenocytes pulsed with an enterobacterial extract....

  13. NAD+ protects against EAE by regulating CD4+ T-cell differentiation

    OpenAIRE

    Tullius, Estefan G.; Biefer, Hector Rodriguez Cetina; Li, Suyan; Trachtenberg, Alexander J.; Edtinger, Karoline; Quante, Markus; Krenzien, Felix; Uehara, Hirofumi; Yang, Xiaoyong; Kissick, Haydn T.; Kuo, Winston P.; Ghiran, Ionita; Fuente García, Miguel Ángel de la; Arredouani, Mohamed S.; Camacho, Virginia

    2014-01-01

    Producción Científica CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNγ(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation th...

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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...

  20. 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.

  1. Antigen presenting B cells facilitate CD4 T cell cooperation resulting in enhanced generation of effector and memory CD4 T cells.

    Directory of Open Access Journals (Sweden)

    David R Kroeger

    Full Text Available We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII-binding peptide of hen egg lysozyme (HEL is facilitated when mice are immunized with splenic antigen presenting cells (APC pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs, can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252 interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of "epitope-spreading" seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation.

  2. Peripheral canine CD4(+)CD8(+) double-positive T cells - unique amongst others.

    Science.gov (United States)

    von Buttlar, Heiner; Bismarck, Doris; Alber, Gottfried

    2015-12-15

    T lymphocytes co-expressing CD4 and CD8 ("double-positive T cells") are commonly associated with a thymic developmental stage of T cells. Their first description in humans and pigs as extrathymic T cells with a memory phenotype almost 30 years ago came as a surprise. Meanwhile peripheral double-positive T cells have been described in a growing number of different species. In this review we highlight novel data from our very recent studies on canine peripheral double-positive T cells which point to unique features of double-positive T cells in the dog. In contrast to porcine CD4(+)CD8(+) T cells forming a homogenous cellular population based on their expression of CD4 and CD8α, canine CD4(+)CD8(+) T cells can be divided into three different cellular subsets with distinct expression levels of CD4 and CD8α. Double-positive T cells expressing CD8β are present in humans and dogs but absent in swine. Moreover, canine CD4(+)CD8(+) T cells can not only develop from CD4(+) single-positive T cells but also from CD8(+) single-positive T cells. Together, this places canine CD4(+)CD8(+) T cells closer to their human than porcine counterparts since human double-positive T cells also appear to be heterogeneous in their CD4 and CD8α expression and have both CD4(+) and CD8(+) T cells as progenitor cells. However, CD4(+) single-positive T cells are the more potent progenitors for canine double-positive T cells, whereas CD8(+) single-positive T cells are more potent progenitors for human double-positive T cells. Canine double-positive T cells have an activated phenotype and may have as yet unrecognized roles in vivo in immunity to infection or in inflammatory diseases such as chronic infection, autoimmunity, allergy, or cancer.

  3. 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

  4. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yong, E-mail: dr_yongchen@hotmail.com [Institute for Advanced Study, Nanchang University, Nanchang, Jiangxi 330031 (China); Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Zeng, Gucheng [Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Chen, Sherry Shiyi [Department of Biomedical Engineering, Duke University, Durham, NC 27708 (United States); Feng, Qian [Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Chen, Zheng Wei, E-mail: zchen@uic.edu [Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2011-04-08

    Highlights: {yields} The unbinding force of sCD4-gp120 interaction was 25.45 {+-} 20.46 pN. {yields} The unbinding force of CD4 antigen-antibody interaction was 51.22 {+-} 34.64 pN. {yields} The unbinding force of gp120 antigen-antibody interaction was 89.87 {+-} 44.63 pN. {yields} The interaction forces between various HIV inhibitors and the target molecules are significantly different. {yields} 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.

  6. 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.

  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;

    1994-01-01

    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. 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. 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

  10. The role of CD4 in antigen-independent activation of isolated single T lymphocytes

    DEFF Research Database (Denmark)

    Kelso, A; Owens, T

    1988-01-01

    The membrane molecule CD4 (L3T4) is thought to facilitate activation of Class II H-2-restricted T cells by binding to Ia determinants on antigen-presenting cells. Recent reports suggest that CD4 can also contribute to antigen-independent activation by anti-T cell receptor (TCR) antibodies. An assay...

  11. 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 ...

  12. CD4-independent use of the CCR5 receptor by sequential primary SIVsm isolates

    Directory of Open Access Journals (Sweden)

    Thorstensson Rigmor

    2007-07-01

    Full Text Available Abstract Background CD4-independence has been taken as a sign of a more open envelope structure that is more accessible to neutralizing antibodies and may confer altered cell tropism. In the present study, we analyzed SIVsm isolates for CD4-independent use of CCR5, mode of CCR5-use and macrophage tropism. The isolates have been collected sequentially from 13 experimentally infected cynomolgus macaques and have previously been shown to use CCR5 together with CD4. Furthermore, viruses obtained early after infection were neutralization sensitive, while neutralization resistance appeared already three months after infection in monkeys with progressive immunodeficiency. Results Depending whether isolated early or late in infection, two phenotypes of CD4-independent use of CCR5 could be observed. The inoculum virus (SIVsm isolate SMM-3 and reisolates obtained early in infection often showed a pronounced CD4-independence since virus production and/or syncytia induction could be detected directly in NP-2 cells expressing CCR5 but not CD4 (CD4-independent-HIGH. Conversely, late isolates were often more CD4-dependent in that productive infection in NP-2/CCR5 cells was in most cases weak and was revealed only after cocultivation of infected NP-2/CCR5 cells with peripheral blood mononuclear cells (CD4-independent-LOW. Considering neutralization sensitivity of these isolates, newly infected macaques often harbored virus populations with a CD4-independent-HIGH and neutralization sensitive phenotype that changed to a CD4-independent-LOW and neutralization resistant virus population in the course of infection. Phenotype changes occurred faster in progressor than long-term non-progressor macaques. The phenotypes were not reflected by macrophage tropism, since all isolates replicated efficiently in macrophages. Infection of cells expressing CCR5/CXCR4 chimeric receptors revealed that SIVsm used the CCR5 receptor in a different mode than HIV-1. Conclusion Our

  13. 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.

  14. 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

  15. Targeting of liposomes to HIV-1-infected cells by peptides derived from the CD4 receptor.

    Science.gov (United States)

    Slepushkin, V A; Salem, I I; Andreev, S M; Dazin, P; Düzgüneş, N

    1996-10-23

    Liposomes can be targeted to HIV-infected cells by either reconstituting transmembrane CD4 in the membrane or covalently coupling soluble CD4 to modified lipids. We investigated whether synthetic peptides could be used as ligands for targeting liposomes. A synthetic peptide from the complementarity determining region 2 (CDR-2)-like domain of CD4 could bind specifically to HIV-infected cells and mediate the binding of peptide-coupled liposomes to these cells. A peptide from the CDR-3-like domain of CD4 inhibited HIV-induced syncytia formation, but failed to target liposomes to infected cells. This apparent discrepancy may be due to the requirement for a conformational change in the CD4 receptor for the CDR-3 region to interact with the HIV envelope protein. Our results demonstrate the feasibility of using synthetic peptides to target liposomes containing antiviral drugs to HIV-infected cells.

  16. 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.

  17. 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...

  18. 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.

  19. The Differentiation and Protective Function of Cytolytic CD4 T Cells in Influenza Infection

    Directory of Open Access Journals (Sweden)

    Deborah M. Brown

    2016-03-01

    Full Text Available CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity (CD4 CTL play a role in chronic, as well as, acute infections such as influenza A virus (IAV infection. In the last couple of decades, techniques to measure the frequency and activity of these cytolytic cells has demonstrated their abundance in infections such as HIV, mouse pox, murine gamma herpes virus, CMV, EBV and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and anti-tumor immunity through their ability to acquire perforin mediated cytolytic activity and contribution to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological relevance of CD4 CTL. Here, we discuss the direct role CD4 CTL play in protection against lethal IAV infection and the factors that drive the generation of perforin mediated lytic activity in CD4 cells in vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other anti-viral and anti-tumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell mediated immune protection against heterosubtypic IAV infection.

  20. 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.

  1. CD4~+Foxp3~+ regulatory T cells converted by rapamycin from peripheral CD4~+ CD25~-naive T cells display more potent regulatory ability in vitro

    Institute of Scientific and Technical Information of China (English)

    CHEN Jian-fei; GAO Jie; ZHANG Dong; WANG Zi-han; ZHU Ji-ye

    2010-01-01

    Background Rapamycin (RAPA) is a relatively new immunosuppressant drug that functions as a serine/threonine kinase inhibitor to prevent rejection in organ transplantation. RAPA blocks activation of T-effector (Teff) cells by inhibiting the response to interleukin-2. Recently, RAPA was also shown to selectively expand the T-regulator (Treg) cell population. To date, no studies have examined the mechanism by which RAPA converts Teff cells to Treg cells. Methods Peripheral CD4~+CD25~- naive T cells were cultivated with RAPA and B cells as antigen-presenting cells (APCs) in vitro. CD4~+CD25~- T cells were harvested after 6 days and analyzed for expression of forkhead box protein 3 (Foxp3) using flow cytometry. CD4~+CD25~+CD127~- subsets as the converted Tregs were isolated from the mixed lymphocyte reactions (MLR) with CD127 negative selection, followed by CD4 and CD25 positive selection using microbeads and magnetic separation column (MSC). Moreover, mRNA was extracted from converted Tregs and C57BL/6 naive CD4~+CD25~+ T cells and Foxp3 levels were examined by quantitative real-time polymerase chain reaction (rt-PCR). A total of 1×10~5 carboxyfluorescein succinimidyl ester (CFSE)-labeled naive CD4~+CD25~- T cells/well from C57BL/6 mice were cocultured with DBA/2 or C3H maturation of dendritic cells (mDCs) (0.25×10~5/well) in 96-well round-bottom plates for 6 days. Then 1×10~5 or 0.25×10~5 converted Treg cells were added to every well as regulatory cells. Cells were harvested after 6 days of culture and analyzed for proliferation of CFSE-labeled naive CD4~+CD25~- T cells using flow cytometry. Data were analyzed using CellQuest software.Results We found that RAPA can convert peripheral CD4~+CD25~- naive T Cells to CD4~+Foxp3~+ Treg cells using B cells as APCs, and this subtype of Treg can potently suppress Teff proliferation and maintain antigenic specificity. Conclusion Our findings provide evidence that RAPA induces Treg cell conversion from Teff cells and

  2. 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.

  3. A novel differentiation pathway from CD4⁺ T cells to CD4⁻ T cells for maintaining immune system homeostasis.

    Science.gov (United States)

    Zhao, X; Sun, G; Sun, X; Tian, D; Liu, K; Liu, T; Cong, M; Xu, H; Li, X; Shi, W; Tian, Y; Yao, J; Guo, H; Zhang, D

    2016-01-01

    CD4(+) T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4(+) T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4(-)CD8(-)NK1.1(-) double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4(+) rather than CD8(+) T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4(+) T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases. PMID:27077809

  4. Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.

    Directory of Open Access Journals (Sweden)

    C Scott Mahan

    Full Text Available BACKGROUND: Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone. METHODOLOGY: This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3 and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB. RESULTS: Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period. CONCLUSION: TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.

  5. Increase in IFNγ(-IL-2(+ cells in recent human CD4 T cell responses to 2009 pandemic H1N1 influenza.

    Directory of Open Access Journals (Sweden)

    Jason M Weaver

    Full Text Available Human CD4 T cell recall responses to influenza virus are strongly biased towards Type 1 cytokines, producing IFNγ, IL-2 and TNFα. We have now examined the effector phenotypes of CD4 T cells in more detail, particularly focusing on differences between recent versus long-term, multiply-boosted responses. Peptides spanning the proteome of temporally distinct influenza viruses were distributed into pools enriched for cross-reactivity to different influenza strains, and used to stimulate antigen-specific CD4 T cells representing recent or long-term memory. In the general population, peptides unique to the long-circulating influenza A/New Caledonia/20/99 (H1N1 induced Th1-like responses biased toward the expression of IFNγ(+TNFα(+ CD4 T cells. In contrast, peptide pools enriched for non-cross-reactive peptides of the pandemic influenza A/California/04/09 (H1N1 induced more IFNγ(-IL-2(+TNFα(+ T cells, similar to the IFNγ(-IL-2(+ non-polarized, primed precursor T cells (Thpp that are a predominant response to protein vaccination. These results were confirmed in a second study that compared samples taken before the 2009 pandemic to samples taken one month after PCR-confirmed A/California/04/09 infection. There were striking increases in influenza-specific TNFα(+, IFNγ(+, and IL-2(+ cells in the post-infection samples. Importantly, peptides enriched for non-cross-reactive A/California/04/09 specificities induced a higher proportion of Thpp-like IFNγ(-IL-2(+TNFα(+ CD4 T cells than peptide pools cross-reactive with previous influenza strains, which induced more Th1 (IFNγ(+TNFα(+ responses. These IFNγ(-IL-2(+TNFα(+ CD4 T cells may be an important target population for vaccination regimens, as these cells are induced upon infection, may have high proliferative potential, and may play a role in providing future effector cells during subsequent infections.

  6. 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

  7. 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.

  8. 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.

  9. 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.

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

    Science.gov (United States)

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

    2011-01-01

    SUMMARY 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 (200 μg) of a murine anti-mouse CD4 monoclonal IgG (clone GK1·5). CD4+ T-cell-depleted hamsters infected with the hookworm Ancylostoma ceylanicum exhibited a threefold higher mean intestinal worm burden and more severe anaemia than animals that received isotype control IgG. In addition, depletion of CD4+ T cells was associated with impaired cellular and humoral (serum and mucosal) immune responses to hookworm antigens. These data demonstrate an effector role for CD4+ T cells in hookworm immunity and disease pathogenesis. Ultimately, these studies may yield important insights into the relationship between intestinal nematode infections and diseases that are associated with CD4+ T-cell depletion, including HIV. PMID:20500671

  11. CD4 lymphocyte dynamics in Tanzanian pulmonary tuberculosis patients with and without hiv co-infection

    Directory of Open Access Journals (Sweden)

    Andersen Aase B

    2012-03-01

    Full Text Available Abstract Background The interaction of HIV and tuberculosis (TB on CD4 levels over time is complex and has been divergently reported. Methods CD4 counts were assessed from time of diagnosis till the end of TB treatment in a cohort of pulmonary TB patients with and without HIV co-infection and compared with cross-sectional data on age- and sex-matched non-TB controls from the same area. Results Of 1,605 study participants, 1,250 were PTB patients and 355 were non-TB controls. At baseline, HIV was associated with 246 (95% CI: 203; 279 cells per μL lower CD4 counts. All PTB patients had 100 cells per μL lower CD4 counts than the healthy controls. The CD4 levels were largely unchanged during a five-month of TB treatment. HIV infected patients not receiving ART at any time and those already on ART at baseline had no increase in CD4 counts after 5 months of TB treatment, whereas those prescribed ART between baseline and 2 months, and between 2 and 5 months increased by 69 (22;117 and 110 (52; 168 CD4 cells per μL after 5 months. Conclusions The increase in circulating CD4 levels observed in PTB in patients is acquired after 2 months of treatment irrespective of HIV status. Initiation of ART is the strongest factor correlated with CD4 increase during TB treatment. Trial registration number Clinical trials.gov: NCT00311298

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

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    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.

  13. 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

  14. 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.

  15. 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.

  16. 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

    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...

  17. 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...

  18. 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......+ cells. Under optimal growth conditions, the initial reduction in antibody binding to CD4 was followed by an apparent re-expression of the CD4 antigen even in the presence of high concentrations of IL-1. This re-expression did not occur if the cells were cultured at 4 degrees C, or after treatment...

  19. 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.

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

    DEFF Research Database (Denmark)

    Julià, Eva; Montalban, Xavier; Al-Zayat, Hammad;

    2006-01-01

    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...... cells expressing CCR5 and CXCR3. RESULTS: In MS patients, the percentage of CD69 was increased and Fas expression decreased in CD4+ CCR5+ T cells. INTERPRETATION: The lower Fas expression in activated CD4+ CCR5+ T cells might contribute to disease pathogenesis by prolonging cell survival and favoring...

  1. 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.

  2. 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

  3. Conformational alterations in the CD4 binding cavity of HIV-1 gp120 influencing gp120-CD4 interactions and fusogenicity of HIV-1 envelopes derived from brain and other tissues

    Directory of Open Access Journals (Sweden)

    Ramsland Paul A

    2011-06-01

    Full Text Available Abstract Background CD4-binding site (CD4bs alterations in gp120 contribute to HIV-1 envelope (Env mediated fusogenicity and the ability of gp120 to utilize low levels of cell-surface CD4. In a recent study, we constructed three-dimensional models of gp120 to illustrate CD4bs conformations associated with enhanced fusogenicity and enhanced CD4-usage of a modestly-sized panel of blood-derived HIV-1 Envs (n = 16. These conformations were characterized by a wider aperture of the CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop. Here, we sought to provide further validation of the utility of these models for understanding mechanisms that influence Env function, by characterizing the structure-function relationships of a larger panel of Envs derived from brain and other tissues (n = 81. Findings Three-dimensional models of gp120 were generated by our recently validated homology modelling protocol. Analysis of predicted CD4bs structures showed correlations between the aperture width of the CD4bs cavity and ability of the Envs to mediate cell-cell fusion, scavenge low-levels of cell-surface CD4, bind directly to soluble CD4, and bind to the Env mAb IgG1b12 whose epitope overlaps the gp120 CD4bs. These structural alterations in the CD4bs cavity were associated with repositioning of the V5 loop. Conclusions Using a large, independent panel of Envs, we can confirm the utility of three-dimensional gp120 structural models for illustrating CD4bs alterations that can affect Env function. Furthermore, we now provide new evidence that these CD4bs alterations augment the ability of gp120 to interact with CD4 by increasing the exposure of the CD4bs.

  4. 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

  5. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics.

    Science.gov (United States)

    Zanetti, Maurizio

    2015-03-01

    Cellular immune responses that protect against tumors typically have been attributed to CD8 T cells. However, CD4 T cells also play a central role. It was shown recently that, in a patient with metastatic cholangiocarcinoma, CD4 T cells specific for a peptide from a mutated region of ERBB2IP could arrest tumor progression. This and other recent findings highlight new opportunities for CD4 T cells in cancer immunotherapy. In this article, I discuss the role and regulation of CD4 T cells in response to tumor Ags. Emphasis is placed on the types of Ags and mechanisms that elicit tumor-protective responses. I discuss the advantages and drawbacks of cancer immunotherapy through personalized genomics. These considerations should help to guide the design of next-generation therapeutic cancer vaccines.

  6. Quantifying CD4/CCR5 Usage Efficiency of HIV-1 Env Using the Affinofile System.

    Science.gov (United States)

    Webb, Nicholas E; Lee, Benhur

    2016-01-01

    Entry of HIV-1 into target cells involves the interaction of the HIV envelope (Env) with both a primary receptor (CD4) and a coreceptor (CXCR4 or CCR5). The relative efficiency with which a particular Env uses these receptors is a major component of cellular tropism in the context of entry and is related to a variety of pathological Env phenotypes (Chikere et al. Virology 435:81-91, 2013). The protocols outlined in this chapter describe the use of the Affinofile system, a 293-based dual-inducible cell line that expresses up to 25 distinct combinations of CD4 and CCR5, as well as the associated Viral Entry Receptor Sensitivity Assay (VERSA) metrics used to summarize the CD4/CCR5-dependent infectivity results. This system allows for high-resolution profiling of CD4 and CCR5 usage efficiency in the context of unique viral phenotypes.

  7. 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

  8. Prevalence of human herpesvirus-8 salivary shedding in HIV increases with CD4 count.

    Science.gov (United States)

    Gandhi, M; Koelle, D M; Ameli, N; Bacchetti, P; Greenspan, J S; Navazesh, M; Anastos, K; Greenblatt, R M

    2004-08-01

    Human herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS), which occurs in epidemic form in human immunodeficiency virus(HIV)-infected individuals. Saliva is the only mucosal fluid in which infectious HHV-8 has been identified, although factors associated with HHV-8 salivary shedding remain unclear. Our study performed PCR analysis for HHV-8 DNA in saliva (and other body fluids) in 66 HIV- and HHV-8-co-infected women without KS so that we could examine predictors for HHV-8 DNA detection. CD4 count was the most significant predictor of HHV-8 salivary shedding, with increased prevalence of HHV-8 salivary DNA at higher CD4 counts. The odds of salivary HHV8 shedding at CD4 counts > = 350 cells/microL was 63 times the odds of shedding at CD4 200. Analysis of these data suggests an increased potential for HHV-8 transmission early in HIV infection, with implications for HHV-8 prevention.

  9. 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-...

  10. 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.

  11. 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.

  12. 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 (...

  13. 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.

  14. The generation and antigen-specificity of CD4+CD25+ regulatory T cells.

    Science.gov (United States)

    Taams, Leonie S; Curnow, S John; Vukmanovic-Stejic, M; Akbar, Arne N

    2006-09-01

    CD4+CD25+ regulatory T cells are essential components of the immune system. They help to maintain immune tolerance by exerting suppressive effects on cells of the adaptive and innate immune system. In the last few years there has been an abundance of papers addressing the suppressive effects of CD4+CD25+ regulatory T cells and their putative role in various experimental disease models and human diseases. Despite the enormous amounts of data on these cells a number of controversial issues still exists. CD4+CD25+ regulatory T cells were originally described as thymus-derived anergic/suppressive T cells. Recent papers however indicate that these cells might also be generated in the periphery. Due to the thymic development of CD4+CD25+ regulatory T cells it was thought that these cells were specific for self-antigens. Indeed it was shown that CD4+CD25+ regulatory T cells could be positively selected upon high affinity interaction with self-antigens. However, evidence is accumulating that these cells might also interact with non-self antigens. Finally, in the literature there is conflicting evidence regarding the role of soluble factors versus cell-contact in the mechanism of suppression. The aim of this review is to summarize the evidence supporting these opposing viewpoints and to combine them into a general model for the origin, function and antigen-specificity of CD4+CD25+ regulatory T cells. PMID:16918478

  15. Interfacial Cavity Filling To Optimize CD4-Mimetic Miniprotein Interactions with HIV-1 Surface Glycoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Morellato-Castillo, Laurence; Acharya, Priyamvada; Combes, Olivier; Michiels, Johan; Descours, Anne; Ramos, Oscar H.P.; Yang, Yongping; Vanham, Guido; Ariën, Kevin K.; Kwong, Peter D.; Martin, Loïc; Kessler, Pascal [ITM-Antwerp; (CEA-CNRS); (NIH)

    2013-08-05

    Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 non-natural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystal structure with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement. Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity.

  16. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing?

    Directory of Open Access Journals (Sweden)

    Kathrin Maly

    2015-01-01

    Full Text Available CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

  17. 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.

  18. The story of CD4+ CD28- T cells revisited: solved or still ongoing?

    Science.gov (United States)

    Maly, Kathrin; Schirmer, Michael

    2015-01-01

    CD4(+)CD28(-) T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4(+) T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4(+)CD28(-) T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4(+)CD28(-) T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4(+)CD28(-) T cell level. The clinical relevance of targeting CD4(+)CD28(-) T cells as a therapeutic option has not been examined so far. PMID:25834833

  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. 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.

  1. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. Correlation between total lymphocyte count, hemoglobin, hematocrit and CD4 count in HIV patients in Nigeria.

    Science.gov (United States)

    Emuchay, Charles Iheanyichi; Okeniyi, Shemaiah Olufemi; Okeniyi, Joshua Olusegun

    2014-04-01

    The expensive and technology limited setting of CD4 count testing is a major setback to the initiation of HAART in a resource limited country like Nigeria. Simple and inexpensive tools such as Hemoglobin (Hb) measurement and Total Lymphocyte Count (TLC) are recommended as substitute marker. In order to assess the correlations of these parameters with CD4 count, 100 "apparently healthy" male volunteers tested HIV positive aged ≥ 20 years but ≤ 40 years were recruited and from whom Hb, Hct, TLC and CD4 count were obtained. The correlation coefficients, R, the Nash-Sutcliffe Coefficient of Efficiency (CoE) and the p-values of the ANOVA model of Hb, Hct and TLC with CD4 count were assessed. The assessments show that there is no significant relationship of any of these parameters with CD4 count and the correlation coefficients are very weak. This study shows that Hb, Hct and TLC cannot be substitute for CD4 count as this might lead to certain individuals' deprivation of required treatment.

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

    DEFF Research Database (Denmark)

    Andersen, Aase B.; Range, Nyagosya; 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 pulmonary TB patients with and without HIV co-infection and compared with cross-sectional data on age- and sex-matched non-TB controls from the same area. RESULTS: Of 1605 study participants, 1250 were PTB patients and 355 were non-TB controls. At baseline, HIV was associated with 246 (95% CI: 203; 279......) cells per uL lower CD4 counts. All PTB patients had 100 cells per uL lower CD4 counts than the healthy controls. The CD4 levels were largely unchanged during five-months of TB treatment. HIV infected patients not receiving ART at any time and those already on ART at baseline had no increase in CD4...

  6. Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells

    Directory of Open Access Journals (Sweden)

    Kim Julian A

    2004-11-01

    Full Text Available Abstract T cell-mediated cancer immunotherapy is dose dependent and optimally requires participation of antigen-specific CD4+ and CD8+ T cells. Here, we isolated tumor-sensitized T cells and activated them in vitro using conditions that led to greater than 108-fold numerical hyperexpansion of either the CD4+ or CD8+ subset while retaining their capacity for in vivo therapeutic efficacy. Murine tumor-draining lymph node (TDLN cells were segregated to purify the CD62Llow subset, or the CD4+ subset thereof. Cells were then propagated through multiple cycles of anti-CD3 activation with IL-2 + IL-7 for the CD8+ subset, or IL-7 + IL-23 for the CD4+ subset. A broad repertoire of TCR Vβ families was maintained throughout hyperexpansion, which was similar to the starting population. Adoptive transfer of hyper-expanded CD8+ T cells eliminated established pulmonary metastases, in an immunologically specific fashion without the requirement for adjunct IL-2. Hyper-expanded CD4+ T cells cured established tumors in intracranial or subcutaneous sites that were not susceptible to CD8+ T cells alone. Because accessibility and antigen presentation within metastases varies according to anatomic site, maintenance of a broad repertoire of both CD4+ and CD8+ T effector cells will augment the overall systemic efficacy of adoptive immunotherapy.

  7. HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

    Directory of Open Access Journals (Sweden)

    Nathan Erdmann

    2015-08-01

    Full Text Available Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1 exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE or its non-adapted (NAE version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001. However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001. CD4+ T cell responses in patients with acute HIV infection (AHI demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

  8. 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

  9. The effect of probiotics on CD4 counts among people living with HIV: a systematic review.

    Science.gov (United States)

    Miller, H; Ferris, R; Phelps, B R

    2016-06-01

    Probiotics are defined by the WHO as 'live microorganisms which when administered in adequate amounts confer a health benefit on the host'. Ongoing research has shown probiotics provide benefits to humans, including protection and restoration of the gastrointestinal and other mucosal tracts. As human immunodeficiency virus (HIV) activates gut-associated lymphoid tissue (GALT), several studies have investigated the effect of probiotics on CD4 cell count and related outcomes among those living with HIV. These studies are summarised here. Manuscripts were identified using the search terms 'probiotics', 'synbiotics', 'HIV', and 'CD4', and were reviewed for relevance and inclusion of CD4 count as an immunologic endpoint. Bibliographies of relevant manuscripts were also reviewed for additional studies matching inclusion and exclusion criteria. The search yielded 91 results; 13 included relevant outcomes. Seven of these studies produced beneficial CD4 outcomes, while the remaining 6 reported on insignificant beneficial or negative CD4 outcomes. The studies summarised here collectively suggest that daily consumption of probiotics over a prolonged period of time may improve CD4 count in people living with HIV.

  10. 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.

  11. 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

    SCID mice express the Fas ligand on the surface. Gut lamina propria CD4+ T cells show Fas-dependent cytotoxicity. A large fraction of gut lamina propria CD4+ T cells that infiltrate the inflamed colon in transplanted SCID mice are activated in situ and many CD4+ T cells are apoptotic. Hence, a large...... fraction of colitis-inducing CD4+ T cells undergo activation-induced cell death in situ and can damage other cells through Fas-dependent cytotoxicity....

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

    Directory of Open Access Journals (Sweden)

    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

  13. 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.

  14. 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

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  18. 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...

  19. Establishment of reference CD4+ T cell values for adult Indian population

    Directory of Open Access Journals (Sweden)

    Ray Krishnangshu

    2011-10-01

    Full Text Available Abstract Background CD4+ T lymphocyte counts are the most important indicator of disease progression and success of antiretroviral treatment in HIV infection in resource limited settings. The nationwide reference range of CD4+ T lymphocytes was not available in India. This study was conducted to determine reference values of absolute CD4+ T cell counts and percentages for adult Indian population. Methods A multicentric study was conducted involving eight sites across the country. A total of 1206 (approximately 150 per/centre healthy participants were enrolled in the study. The ratio of male (N = 645 to female (N = 561 of 1.14:1. The healthy status of the participants was assessed by a pre-decided questionnaire. At all centers the CD4+ T cell count, percentages and absolute CD3+ T cell count and percentages were estimated using a single platform strategy and lyse no wash technique. The data was analyzed using the Statistical Package for the Social Scientist (SPSS, version 15 and Prism software version 5. Results The absolute CD4+ T cell counts and percentages in female participants were significantly higher than the values obtained in male participants indicating the true difference in the CD4+ T cell subsets. The reference range for absolute CD4 count for Indian male population was 381-1565 cells/μL and for female population was 447-1846 cells/μL. The reference range for CD4% was 25-49% for male and 27-54% for female population. The reference values for CD3 counts were 776-2785 cells/μL for Indian male population and 826-2997 cells/μL for female population. Conclusion The study used stringent procedures for controlling the technical variation in the CD4 counts across the sites and thus could establish the robust national reference ranges for CD4 counts and percentages. These ranges will be helpful in staging the disease progression and monitoring antiretroviral therapy in HIV infection in India.

  20. 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...

  1. Increased soluble CD4 in serum of rheumatoid arthritis patients is generated by matrix metalloproteinase (MMP-like proteinases.

    Directory of Open Access Journals (Sweden)

    Wen-Yi Tseng

    Full Text Available Higher soluble CD4 (sCD4 levels in serum have been detected in patients of infectious and chronic inflammatory diseases. However, how and why sCD4 is produced remains poorly understood. We establish sensitive ELISA and WB assays for sCD4 detection in conditioned medium of in vitro cell culture system and serum of chronic inflammatory patients. Serum samples from patients with systemic lupus erythematosus (SLE (n = 79, rheumatoid arthritis (RA (n = 59, ankylosing spondylitis (AS (n = 25, gout (n = 31, and normal controls (n = 99 were analyzed using ELISA for sCD4 detection. Results from each assay were analyzed by the Kruskal-Wallis test. Dunn's multiple comparison post-test was then applied between groups. We confirm that cells expressing exogenous CD4 produce sCD4 in a constitutive and PMA-induced manner. Importantly, sCD4 production in a heterologous expression system is inhibited by GM6001 and TAPI-0, suggesting receptor shedding by matrix metalloproteinase (MMP-like proteinases. Moreover, similar findings are recapitulated in human primary CD4(+ T cells. Finally, we show that serum sCD4 levels are increased in patients of chronic inflammatory diseases including RA and SLE, but not in those with gout. Intriguingly, sCD4 levels in RA patients are correlated positively with the disease activities and higher sCD4 levels seem to associate with poor prognosis. Taken together, we conclude that CD4 is shed from cell surface by a MMP-like sheddase and sCD4 level is closely related with the inflammatory condition in certain chronic diseases. Hence, sCD4 might be considered an important parameter for RA disease progression with potential diagnostic importance.

  2. CD+4CD+25调节性T细胞与肿瘤的相关性研究%CD+4 CD+25 regulatory T cells and lung cancer

    Institute of Scientific and Technical Information of China (English)

    翟晋芳; 韩福才

    2009-01-01

    通过了解CD+4 CD+25调节性T细胞(CD+4 CD+25Treg)表面分子的特性和CD+4 CD+25Treg在外周血和组织中的表达,认识CD+4 CD+25 Treg在肿瘤免疫凋节中的作用,探索其作用的分子机制.%To know CD+4 CD+25 regulatory T cells' s function in tumor immunological regulation and to search for its functionary molecule mechanism by reviewing researches associated with the characteristics of CD+4 CD+25 regulatory T cells surface molecules and the expression of CD+4 CD+25 regulatory T cells in the peripheral blood and tissues.

  3. 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

  4. Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis.

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    Zili Zhang

    Full Text Available BACKGROUND: T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2 plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function. DESIGN AND METHODS: Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU models. RESULTS: In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis. CONCLUSION: These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis.

  5. Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis.

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    Bingfen Yang

    Full Text Available CD244 (2B4 is a member of the signaling lymphocyte activation molecule (SLAM family of immune cell receptors and it plays an important role in modulating NK cell and CD8(+ T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4(+ T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4(+ T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen-specific CD4(+ T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4(+ T cells, CD244/2B4-bright CD4(+ T cell subset had significantly reduced expression of IFN-γ, suggesting that CD244/2B4 expression may modulate IFN-γ production in M. tuberculosis antigen-responsive CD4(+ T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-γ. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-γ, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4(+ T cell function.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy.

    Science.gov (United States)

    Matsuzawa, Yu; Oshima, Shigeru; Takahara, Masahiro; Maeyashiki, Chiaki; Nemoto, Yasuhiro; Kobayashi, Masanori; Nibe, Yoichi; Nozaki, Kengo; Nagaishi, Takashi; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Ma, Averil; Watanabe, Mamoru

    2015-01-01

    Autophagy plays important roles in metabolism, differentiation, and survival in T cells. TNFAIP3/A20 is a ubiquitin-editing enzyme that is thought to be a negative regulator of autophagy in cell lines. However, the role of TNFAIP3 in autophagy remains unclear. To determine whether TNFAIP3 regulates autophagy in CD4 T cells, we first analyzed Tnfaip3-deficient naïve CD4 T cells in vitro. We demonstrated that Tnfaip3-deficient CD4 T cells exhibited reduced MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) puncta formation, increased mitochondrial content, and exaggerated reactive oxygen species (ROS) production. These results indicate that TNFAIP3 promotes autophagy after T cell receptor (TCR) stimulation in CD4 T cells. We then investigated the mechanism by which TNFAIP3 promotes autophagy signaling. We found that TNFAIP3 bound to the MTOR (mechanistic target of rapamycin) complex and that Tnfaip3-deficient cells displayed enhanced ubiquitination of the MTOR complex and MTOR activity. To confirm the effects of enhanced MTOR activity in Tnfaip3-deficient cells, we analyzed cell survival following treatment with Torin1, an MTOR inhibitor. Tnfaip3-deficient CD4 T cells exhibited fewer cell numbers than the control cells in vitro and in vivo. In addition, the impaired survival of Tnfaip3-deficient cells was ameliorated with Torin1 treatment in vitro and in vivo. The effect of Torin1 was abolished by Atg5 deficiency. Thus, enhanced MTOR activity regulates the survival of Tnfaip3-deficient CD4 T cells. Taken together, our findings illustrate that TNFAIP3 restricts MTOR signaling and promotes autophagy, providing new insight into the manner in which MTOR and autophagy regulate survival in CD4 T cells.

  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. 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

  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. Selective Loss of Innate CD4+ Vα24 Natural Killer T Cells in Human Immunodeficiency Virus Infection

    Science.gov (United States)

    Sandberg, Johan K.; Fast, Noam M.; Palacios, Emil H.; Fennelly, Glenn; Dobroszycki, Joanna; Palumbo, Paul; Wiznia, Andrew; Grant, Robert M.; Bhardwaj, Nina; Rosenberg, Michael G.; Nixon, Douglas F.

    2002-01-01

    Vα24 natural killer T (NKT) cells are innate immune cells involved in regulation of immune tolerance, autoimmunity, and tumor immunity. However, the effect of human immunodeficiency virus type 1 (HIV-1) infection on these cells is unknown. Here, we report that the Vα24 NKT cells can be subdivided into CD4+ or CD4− subsets that differ in their expression of the homing receptors CD62L and CD11a. Furthermore, both CD4+ and CD4− NKT cells frequently express both CXCR4 and CCR5 HIV coreceptors. We find that the numbers of NKT cells are reduced in HIV-infected subjects with uncontrolled viremia and marked CD4+ T-cell depletion. The number of CD4+ NKT cells is inversely correlated with HIV load, indicating depletion of this subset. In contrast, CD4− NKT-cell numbers are unaffected in subjects with high viral loads. HIV infection experiments in vitro show preferential depletion of CD4+ NKT cells relative to regular CD4+ T cells, in particular with virus that uses the CCR5 coreceptor. Thus, HIV infection causes a selective loss of CD4+ lymph node homing (CD62L+) NKT cells, with consequent skewing of the NKT-cell compartment to a predominantly CD4− CD62L− phenotype. These data indicate that the key immunoregulatory NKT-cell compartment is compromised in HIV-1-infected patients. PMID:12097565

  12. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    Science.gov (United States)

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Memory CD4+ T cells do not induce graft-versus-host disease.

    Science.gov (United States)

    Anderson, Britt E; McNiff, Jennifer; Yan, Jun; Doyle, Hester; Mamula, Mark; Shlomchik, Mark J; Shlomchik, Warren D

    2003-07-01

    Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Donor T cells that accompany stem cell grafts cause GVHD by attacking recipient tissues; therefore, all patients receive GVHD prophylaxis by depletion of T cells from the allograft or through immunosuppressant drugs. In addition to providing a graft-versus-leukemia effect, donor T cells are critical for reconstituting T cell-mediated immunity. Ideally, immunity to infectious agents would be transferred from donor to host without GVHD. Most donors have been exposed to common pathogens and have an increased precursor frequency of memory T cells against pathogenic antigens. We therefore asked whether memory CD62L-CD44+ CD4+ T cells would induce less GVHD than unfractionated or naive CD4+ T cells. Strikingly, we found that memory CD4 cells induced neither clinical nor histologic GVHD. This effect was not due to the increased number of CD4+CD25+ regulatory T cells found in the CD62L-CD44+ fraction because memory T cells depletion of these cells did not cause GVHD. Memory CD4 cells engrafted and responded to antigen both in vivo and in vitro. If these murine results are applicable to human alloSCT, selective administration of memory T cells could greatly improve post-transplant immune reconstitution.

  15. Computational modeling of heterogeneity and function of CD4+ T cells

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    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.

  16. Immature CD4+ dendritic cells conditioned with donor kidney antigen prolong renal allograft survival in rats

    Institute of Scientific and Technical Information of China (English)

    WANG Tao; XU Lin; LI Heng; HUANG Zheng-yu; ZHANG Sheng-ping; MIAO Bin; NA Ning

    2012-01-01

    Background AIIogeneic transplant rejection is currently a major problem encountered during organ transplantation.The dendritic cell (DC) is the most effective powerful known professional antigen-presenting cell,and recent studies have found that DCs can also induce immune tolerance,and avoid or reduce the degree of transplant rejection.The aim of this study was to evaluate the effect of transfused immature CD4+ DCs on renal allografts in the rat model.Methods In this study,we induced CD4+ immature DCs from rat bone marrow cells by a cytokine cocktail.The immature CD4+ DCs were identified by morphological analysis and then the suppressive activity of these cells conditioned with donor kidney antigen was evaluated in vitro and in vivo.Results Immature CD4+ DCs conditioned with donor kidney antigen possessed immunosuppressive activity in vitro and they were able to prolong renal transplant survival in an allograft rat model in vivo.Conclusions Our study provides new information on efficacious renal transplantation,which might be useful for understanding the function of immature CD4+ DCs in modulating renal transplant rejection and improving clinical outcome in future studies.

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

    Energy Technology Data Exchange (ETDEWEB)

    Schols, D.; Baba, M.; Pauwels, R.; Desmyter, J.; De Clercq, E. (Katholieke Universiteit Leuven (Belgium))

    1989-05-01

    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 {mu}M in various T4{sup +} 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.

  18. 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

  19. 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.

  20. Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell–mediated immunity

    Science.gov (United States)

    Flies, Dallas B.; Han, Xue; Higuchi, Tomoe; Zheng, Linghua; Sun, Jingwei; Ye, Jessica Jane; Chen, Lieping

    2014-01-01

    T cell activation is regulated by the interactions of surface receptors with stimulatory and inhibitory ligands. Programmed death-1 homolog (PD-1H, also called VISTA) is a member of the CD28 family of proteins and has been shown to act as a coinhibitory ligand on APCs that suppress T cell responses. Here, we determined that PD-1H functions as a coinhibitory receptor for CD4+ T cells. CD4+ T cells in mice lacking PD-1H exhibited a dramatically increased response to antigen stimulation. Furthermore, delivery of a PD-1H–specific agonist mAb directly inhibited CD4+ T cell activation both in vitro and in vivo, validating a coinhibitory function of PD-1H. In a murine model of acute hepatitis, administration of a PD-1H agonist mAb suppressed CD4+ T cell–mediated acute inflammation. PD-1H–deficient animals were highly resistant to tumor induction in a murine brain glioma model, and depletion of CD4+ T cells, but not CD8+ T cells, promoted tumor formation. Together, our findings suggest that PD-1H has potential as a target of immune modulation in the treatment of human inflammation and malignancies. PMID:24743150

  1. 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

  2. The Fc and not CD4 Receptor Mediates Antibody Enhancement of HIV Infection in Human Cells

    Science.gov (United States)

    Homsy, Jacques; Meyer, Mia; Tateno, Masatoshi; Clarkson, Sarah; Levy, Jay A.

    1989-06-01

    Antibodies that enhance human immunodeficiency virus (HIV) infectivity have been found in the blood of infected individuals and in infected or immunized animals. These findings raise serious concern for the development of a safe vaccine against acquired immunodeficiency syndrome. To address the in vivo relevance and mechanism of this phenomenon, antibody-dependent enhancement of HIV infectivity in peripheral blood macrophages, lymphocytes, and human fibroblastoid cells was studied. Neither Leu3a, a monoclonal antibody directed against the CD4 receptor, nor soluble recombinant CD4 even at high concentrations prevented this enhancement. The addition of monoclonal antibody to the Fc receptor III (anti-FcRIII), but not of antibodies that react with FcRI or FcRII, inhibited HIV type 1 and HIV type 2 enhancement in peripheral blood macrophages. Although enhancement of HIV infection in CD4+ lymphocytes could not be blocked by anti-FcRIII, it was inhibited by the addition of human immunoglobulin G aggregates. The results indicate that the FcRIII receptor on human macrophages and possibly another Fc receptor on human CD4+ lymphocytes mediate antibody-dependent enhancement of HIV infectivity and that this phenomenon proceeds through a mechanism independent of the CD4 protein.

  3. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.

    Science.gov (United States)

    Swaims, Alison Y; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I; Devadas, Satish; Shi, Yufang; Rabson, Arnold B

    2010-10-21

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals. PMID:20634377

  4. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus.

    Directory of Open Access Journals (Sweden)

    Jie Dong

    Full Text Available After a tightly regulated developmental program in the thymus, "mature" single positive (SP thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4(+ pre-RTEs, a population of CD4(+ SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4(+ pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs' better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4(+ pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4(+ pre-RTEs is independent of MHC class II and Aire molecules.

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

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    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

  6. 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

  7. Reconstitution of CD4 T Cells in Bronchoalveolar Lavage Fluid after Initiation of Highly Active Antiretroviral Therapy▿

    Science.gov (United States)

    Knox, Kenneth S.; Vinton, Carol; Hage, Chadi A.; Kohli, Lisa M.; Twigg, Homer L.; Klatt, Nichole R.; Zwickl, Beth; Waltz, Jeffrey; Goldman, Mitchell; Douek, Daniel C.; Brenchley, Jason M.

    2010-01-01

    The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells. PMID:20610726

  8. Dynamic transcription of long non-coding RNA genes during CD4+ T cell development and activation.

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    Fei Xia

    Full Text Available BACKGROUND: Recent evidence shows that long non-coding RNA (LncRNA play important regulatory roles in many biology process, including cell development, activation and oncogenesis. However, the roles of these LncRNAs in the development and activation of CD4+ T cells, which is an important component of immune response, remain unknown. RESULTS: To predict the function of LncRNA in the development and activation of CD4+ T cells, first, we examined the expression profiles of LncRNAs and mRNAs in CD4-CD8- (DN, CD4+CD8+ (DP, CD4+CD8-, and activated CD4+CD8- T cells in a microarray analysis and verified these results by real time PCRs (qPCR. We found that the expression of hundreds of LncRNAs significantly changed in each process of developmental transition, including DN into DP, DP into CD4+CD8-, and CD4+CD8- into activated CD4+ T cells. A Kendall distance analysis suggested that the expression of LncRNAs in DN, DP, CD4+CD8- T cells and activated CD4+ T cells were correlated with the expression of mRNAs in these T cells. The Blat algorithm and GO analysis suggested that LncRNAs may exert important roles in the development and activation of CD4+ T cells. These roles included proliferation, homeostasis, maturation, activation, migration, apoptosis and calcium ion transportation. CONCLUSION: The present study found that the expression profiles of LncRNAs in different stages of CD4+ T cells are distinguishable. LncRNAs are involved in the key biological process in CD4+ T cell development and activation.

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

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    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.

  10. 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

  11. 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

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

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    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

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

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    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

  14. Differential role of CD4+ cells in the sensitization and effector phases of accelerated graft rejection.

    Science.gov (United States)

    Sablinski, T; Sayegh, M H; Hancock, W W; Kut, J P; Kwok, C A; Milford, E L; Tilney, N L; Kupiec-Weglinski, J W

    1991-01-01

    Although CD4-targeted therapy markedly prolongs survival of organ allografts in naive rodents, its effects in primed hosts have not been studied. In our model of accelerated rejection (ACCR) of cardiac Tx in rats, treatment with BWH-4, a CD4 mAb (IgG2a), in the sensitization (between skin and heart Tx) but not in the effector (after cardiac Tx) phase, abrogated fulminant less than 36 hr rejection response and prolonged Tx survival to ca. 11 days. This effect correlated with decreased frequency of circulating CD4+ cells, but it did not depend upon their total depletion. It was also related to BWH-4 mAb-mediated elimination/depression of strong anti-donor humoral responses and cellular responses as determined by lymphocyte-mediated cytotoxicity and mixed lymphocyte reaction and mounted otherwise at the time of engraftment by untreated sensitized hosts. Immunoperoxidase studies of cardiac Tx from BWH-4-conditioned recipients revealed reduced T and B cell activities, reflected in abolition/reduction in deposition of humoral mediators, infiltrating cells, intra-Tx elaboration of interleukin-2 and interferon-gamma, and cell activation. This first report of the successful use of CD4 mAb in sensitized recipients of vascularized organ Tx, stresses the role of CD4+ cells as potential targets for immunosuppression in the sensitization phase of accelerated Tx injury. The beneficial therapeutic effect, probably due to both depletion and functional inhibition of CD4+ T cells, has been achieved by using relatively low doses of BWH-4 mAb. PMID:1824805

  15. 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.).

  16. 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...

  17. 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...

  18. 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...

  19. Differential human immunodeficiency virus expression in CD4+ cloned lymphocytes: from viral latency to replication.

    Science.gov (United States)

    Chapel, A; Bensussan, A; Vilmer, E; Dormont, D

    1992-06-01

    By using cloning methodology, 13 CD4+, CD8-, CD45RO+, and CD29+ clones, isolated from human immunodeficiency virus (HIV)-negative donors, have been characterized and tested regarding their susceptibility to two strains of HIV type 1 (HIV-1). Infected clones possess integrated provirus. Only six are able to replicate HIV-1, while seven may normally grow without cytopathic effect and without viral replication. These results argue that all CD4+ lymphocyte clones may be infectable but that a heterogeneity exists regarding their abilities to replicate HIV-1.

  20. 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

  1. Antiretroviral treatment cohort analysis using time-updated CD4 counts: assessment of bias with different analytic methods.

    Directory of Open Access Journals (Sweden)

    Katharina Kranzer

    Full Text Available BACKGROUND: Survival analysis using time-updated CD4+ counts during antiretroviral therapy is frequently employed to determine risk of clinical events. The time-point when the CD4+ count is assumed to change potentially biases effect estimates but methods used to estimate this are infrequently reported. METHODS: This study examined the effect of three different estimation methods: assuming i a constant CD4+ count from date of measurement until the date of next measurement, ii a constant CD4+ count from the midpoint of the preceding interval until the midpoint of the subsequent interval and iii a linear interpolation between consecutive CD4+ measurements to provide additional midpoint measurements. Person-time, tuberculosis rates and hazard ratios by CD4+ stratum were compared using all available CD4+ counts (measurement frequency 1-3 months and 6 monthly measurements from a clinical cohort. Simulated data were used to compare the extent of bias introduced by these methods. RESULTS: The midpoint method gave the closest fit to person-time spent with low CD4+ counts and for hazard ratios for outcomes both in the clinical dataset and the simulated data. CONCLUSION: The midpoint method presents a simple option to reduce bias in time-updated CD4+ analysis, particularly at low CD4 cell counts and rapidly increasing counts after ART initiation.

  2. 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.

  3. Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes

    Science.gov (United States)

    Pérez-Santiago, Josué; Ouchi, Dan; Urrea, Victor; Carrillo, Jorge; Cabrera, Cecilia; Villà-Freixa, Jordi; Puig, Jordi; Paredes, Roger; Negredo, Eugènia; Clotet, Bonaventura; Massanella, Marta; Blanco, Julià

    2016-01-01

    Background: The failure to increase CD4+ T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4+ T-cell homeostasis and impacts clinical evolution. Methods: We evaluated different definitions of immunodiscordance based on CD4+ T-cell counts (cutoff) or CD4+ T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals. Results: Cutoff definition of CD4+ cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4+ T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4+ T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4+ T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4+ values were maintained in these participants over time. Conclusion: A cutoff value of CD4+ T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup

  4. Brief Report: Enhanced Normalization of CD4/CD8 Ratio With Earlier Antiretroviral Therapy at Primary HIV Infection

    Science.gov (United States)

    Inshaw, Jamie; Kaleebu, Pontiano; Cooper, David; Ramjee, Gita; Schechter, Mauro; Tambussi, Giuseppe; Fox, Julie; Samuel, Miriam; Miro, Jose M.; Weber, Jonathan; Porter, Kholoud; Fidler, Sarah

    2016-01-01

    Background: Total CD4+ T-cell counts predict HIV disease progression but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker of immune dysfunction, a prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite antiretroviral therapy (ART), recovery of CD4/CD8 ratio in chronic HIV infection is incomplete; we hypothesize enhanced CD4/CD8 ratio recovery with earlier treatment initiation in recently infected individuals. Methods: CD4+ count and CD4/CD8 ratio were analyzed using data from 2 cohorts: SPARTAC trial and the UK HIV Seroconverters Cohort where primary HIV infection (PHI) was defined as within 6 months from estimated date of infection. Using time-to-event methods and Cox proportional hazard models, we examined the effect of CD4/CD8 ratio at seroconversion on disease progression (CD4 1.0). Findings: Of 573 seroconverters, 482 (84%) had abnormal CD4/CD8 ratios at HIV seroconversion. Individuals with higher CD4/CD8 ratio at seroconversion were significantly less likely to reach the disease progression endpoint [adjusted hazard ratio (aHR) (95% CI) = 0.52 (0.32 to 0.82), P = 0.005]. The longer the interval between seroconversion and ART initiation [HR (95% CI) = 0.98 per month increase (0.97, 0.99), P < 0.001], the less likely the CD4/CD8 ratio normalization. ART initiation within 6 months from seroconversion was significantly more likely to normalize [HR (95% CI) = 2.47 (1.67 to 3.67), P < 0.001] than those initiating later. Interpretation: Most individuals presenting in PHI have abnormal CD4/CD8 ratios. The sooner the ART is initiated in PHI, the greater the probability of achieving normal CD4/CD8 ratio. PMID:27070122

  5. 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

  6. 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.

  7. Association of progressive CD4(+ T cell decline in SIV infection with the induction of autoreactive antibodies.

    Directory of Open Access Journals (Sweden)

    Takeo Kuwata

    2009-04-01

    Full Text Available The progressive decline of CD4(+ T cells is a hallmark of disease progression in human immunodeficiency virus (HIV and simian immunodeficiency virus (SIV infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+ T cells, chronic infection is often associated with a progressive decline of total CD4(+ T cells, including the naïve subset. The mechanism of this second phase of CD4(+ T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+ T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+ T cells demonstrated two patterns of CD4(+ T cell depletion, primarily affecting either naïve or memory CD4(+ T cells. Progressive decline of total CD4(+ T cells was observed only in macaques with naïve CD4(+ T cell depletion (ND, though the depletion of memory CD4(+ T cells was profound in macaques with memory CD4(+ T cell depletion (MD. ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4(+ T cells was associated with plasma antibodies autoreactive with CD4(+ T cells, increasing numbers of IgG-coated CD4(+ T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa, dsDNA, and phospholipid (aPL. Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4(+ T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+ T cell decline

  8. IL-35, an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells.

    Science.gov (United States)

    Castellani, Maria Luisa; Anogeianaki, A; Felaco, P; Toniato, E; De Lutiis, M A; Shaik, B; Fulcheri, M; Vecchiet, J; Tetè, S; Salini, V; Theoharides, T C; Caraffa, A; Antinolfi, P; Frydas, I; Conti, P; Cuccurullo, C; Ciampoli, C; Cerulli, G; Kempuraj, D

    2010-01-01

    Interleukin 12 (IL 12) p35/p40 is a heterodimeric cytokine which plays a critical role in inflammation, immunity and tissue proliferation, and also plays a relevant function in T helper (Th) cell polarization and Th1 T-cell differentiation. IL-12 family members, IL-12p70, IL-23, IL-27 and IL-35, play an important role in influencing helper T-cell differentiation. EBV-induced gene 3 can be associated with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, also called IL-35. It has been shown that IL-35 has biological activity and able to expand CD4+CD25+ Treg cells, suppress the proliferation of CD4+CD25- effector cells and inhibit Th17 cell polarization. IL-35 has been shown to be constitutively expressed by regulatory T (Treg) cells CD4(+)CD25(+)Foxp3(+) and suggested to contribute to their suppressive activity. IL-35 is a crucial mediator which provokes CD4+CD25+ T cell proliferation and IL-10 generation, another well-known anti-inflammatory cytokine, along with TGFbeta cytokine. These studies suggest that IL-35, together with other successfully discovered cytokine inhibitors, represents a new potential therapeutic cytokine for chronic inflammation, autoimmunity and other immunological disorders.

  9. 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

  10. 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

  11. 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...

  12. Aging disturbs the balance between effector and regulatory CD4+T cells

    NARCIS (Netherlands)

    van der Geest, Kornelis S. M.; Abdulahad, Wayel H.; Tete, Sarah M.; Lorencetti, Pedro G.; Horst, Gerda; Bos, Nicolaas A.; Kroesen, Bart-Jan; Brouwer, Elisabeth; Boots, Annemieke M. H.

    2014-01-01

    Healthy aging requires an optimal balance between pro-inflammatory and anti-inflammatory immune responses. Although CD4+ T cells play an essential role in many immune responses, few studies have directly assessed the effect of aging on the balance between effector T (Teff) cells and regulatory T (Tr

  13. 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...

  14. 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...

  15. 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 ...

  16. 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.

  17. CD4 Cell Counts at HIV Diagnosis among HIV Outpatient Study Participants, 2000–2009

    Directory of Open Access Journals (Sweden)

    Kate Buchacz

    2012-01-01

    Full Text Available Background. It is unclear if CD4 cell counts at HIV diagnosis have improved over a 10-year period of expanded HIV testing in the USA. Methods. We studied HOPS participants diagnosed with HIV infection ≤6 months prior to entry into care during 2000–2009. We assessed the correlates of CD4 count <200 cells/mm3 at HIV diagnosis (late HIV diagnosis by logistic regression. Results. Of 1,203 eligible patients, 936 (78% had a CD4 count within 3 months after HIV diagnosis. Median CD4 count at HIV diagnosis was 299 cells/mm3 and did not significantly improve over time (P=0.13. Comparing periods 2000-2001 versus 2008-2009, respectively, 39% and 35% of patients had a late HIV diagnosis (P=0.34. Independent correlates of late HIV diagnosis were having an HIV risk other than being MSM, age ≥35 years at diagnosis, and being of nonwhite race/ethnicity. Conclusions. There is need for routine universal HIV testing to reduce the frequency of late HIV diagnosis and increase opportunity for patient- and potentially population-level benefits associated with early antiretroviral treatment.

  18. 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

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

    DEFF Research Database (Denmark)

    Jensen, J; Langkilde, Annika Reynberg; Fenst, C;

    2004-01-01

    severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states...

  20. 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.

  1. Changes in CD4 count among persons living with HIV/AIDS following Hurricane Katrina.

    Science.gov (United States)

    Robinson, William T; Wendell, Deborah; Gruber, DeAnn

    2011-07-01

    To examine the effects of Hurricane Katrina on the disease progression of persons living with HIV/AIDS (PLWH/A), CD4 counts during the 18 months immediately prior and subsequent to Katrina were obtained from the Louisiana Office of Public Health. PLWH/A were determined to be either non-residents of the New Orleans area, returning evacuees or evacuees who had returned to the area within 18 months. A mixed model repeated measures ANOVA showed significant effects for race, sex, age, year of diagnosis, and mode of exposure. A significant main effect for residence was found, as well as an interaction of residence by time of CD4 count (pre-Katrina vs. post-Katrina), indicating that, while non-returning evacuees had lower overall CD4 counts, the change in CD4 counts of non-returning evacuees dropped more sharply than those of the returning PLWH/A or non-residents. While these results point to a potential need for the population of PLWH/A who continue to be affected by Katrina, they also provide important data on the effect that large-scale disasters and stressful life events may have on individuals with chronic disease.

  2. 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

  3. 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)

  4. 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 ...

  5. 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...

  6. Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Michal Kuczma

    Full Text Available The presence of Foxp3(+ regulatory CD4(+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral T(reg cells represent T(reg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4(+ T cells and thus representing adaptive T(reg cells. The generation of T(reg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of T(reg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied T(reg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4(+ T cells and which preserve the heterogeneity of the T(reg population. The majority of T(reg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4(+ T cells. A small T(reg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and T(reg cells. However, the population of T(reg cells in tumors was dominated by cells expressing TCRs shared with effector CD4(+ T cells. In contrast, T(reg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all T(reg cells in tumor lesions. Our results suggest that the T(reg repertoire in tumors is generated by conversion of effector CD4(+ T cells or expansion of a minor subset of T(reg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4(+ T cells and/or selectively inhibiting the expansion of a minor T(reg subset.

  7. 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

  8. 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.

    2016-01-01

    ABSTRACT 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

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64(+) cells.

    Science.gov (United States)

    Vogel, Stephanie; Grabski, Elena; Buschjäger, Daniela; Klawonn, Frank; Döring, Marius; Wang, Junxi; Fletcher, Erika; Bechmann, Ingo; Witte, Torsten; Durisin, Martin; Schraven, Burkhart; Mangsbo, Sara M; Schönfeld, Kurt; Czeloth, Niklas; Kalinke, Ulrich

    2015-12-16

    Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64(+) monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients' inflamed joints that comprised enhanced numbers of CD64(+) cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64(+) cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64(+) cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions.

  18. 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...... plasma cells were present in the lamina propria of both the small and large intestine. We conclude that low numbers of intraveneously transferred CD4+ T cells induce IBD in SCID mice. In the late stages of CD4+ T cell-induced IBD, the colonic lamina propria becomes infiltrated with macrophages...

  19. 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

  20. Surface membrane CD4 turnover in phorbol ester stimulated T-lymphocytes. Evidence of degradation and increased synthesis

    DEFF Research Database (Denmark)

    Møller, B K; Andresen, B S; Christensen, E I;

    1990-01-01

    Down-regulation of surface membrane CD4 (smCD4) in phorbol ester stimulated T-cells resulted from internalization. Internalization (T1/2 = 15 min at 50 ng PMA/ml) was followed by degradation of CD4-bound antibodies. Degradation in unstimulated T-cells was comparatively insignificant. Release of d...... than recycling contributed to an accelerated smCD4 turnover in activated cells.......Down-regulation of surface membrane CD4 (smCD4) in phorbol ester stimulated T-cells resulted from internalization. Internalization (T1/2 = 15 min at 50 ng PMA/ml) was followed by degradation of CD4-bound antibodies. Degradation in unstimulated T-cells was comparatively insignificant. Release...... of degradation products was PMA dose-dependent and could be inhibited by methylamine. Uptake and degradation continued after maximal down-regulation of surface membrane CD4, and methylamine did not inhibit reappearance of smCD4 antigens. Metabolic labelling of T-cells further showed that ongoing synthesis rather...

  1. 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 ...

  2. 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 ...

  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)

    ... Cervical cancer is caused by a virus called HPV. The virus spreads through sexual contact. Most women's bodies are able to fight HPV infection. But sometimes the virus leads to cancer. You're at higher risk ...

  5. 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, ...

  6. 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.

  7. 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

  8. 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...

  9. 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

  10. 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

  11. 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

  12. Targeted infection of HIV-1 Env expressing cells by HIV(CD4/CXCR4 vectors reveals a potential new rationale for HIV-1 mediated down-modulation of CD4

    Directory of Open Access Journals (Sweden)

    Harmison George G

    2005-12-01

    Full Text Available Abstract Background Efficient targeted gene transfer and cell type specific transgene expression are important for the safe and effective expression of transgenes in vivo. Enveloped viral vectors allow insertion of exogenous membrane proteins into their envelopes, which could potentially aid in the targeted transduction of specific cell types. Our goal was to specifically target cells that express the T cell tropic HIV-1 envelope protein (Env using the highly specific interaction of Env with its cellular receptor (CD4 inserted into the envelope of an HIV-1-based viral vector. Results To generate HIV-1-based vectors carrying the CD4 molecule in their envelope, the CD4 ectodomain was fused to diverse membrane anchors and inserted together with the HIV-1 coreceptor CXCR4 into the envelopes of HIV-1 vector particles. Independent of the type of CD4 anchor, all chimeric CD4 proteins inserted into HIV-1 vector envelopes and the resultant HIV(CD4/CXCR4 particles were able to selectively confer neomycin resistance to cells expressing the fusogenic T cell tropic HIV-1 Env protein. Unexpectedly, in the absence of Env on the target cells, all vector particles carrying the CD4 ectodomain anchored in their envelope adhered to various cell types without infecting these cells. This cell adhesion was very avid. It was independent of the presence of Env on the target cell, the type of CD4 anchor or the presence of CXCR4 on the particle. In mixed cell populations with defined ratios of Env+/Env- cells, the targeted transduction of Env+ cells by HIV(CD4/CXCR4 particles was diminished in proportion to the number of Env- cells. Conclusion Vector diversion caused by a strong, non-selective cell binding of CD4+-vector particles effectively prevents the targeted transduction of HIV-1 Env expressing cells in mixed cell populations. This Env-independent cell adhesion severely limits the effective use of targeted HIV(CD4/CXCR4 vectors designed to interfere with HIV-1

  13. 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

  14. 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...

  15. 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

    Many novel vaccine strategies rely on recombinant viral vectors for antigen delivery, and adenovirus vectors have emerged among the most potent of these. In this report, we have compared the immune response induced through priming with adenovirus vector-encoded full-length viral protein...... to that 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...... in the 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...

  16. Detection of CD4+ T-lymphocytes from hemodialyzed patients by surface plasmon resonance

    Institute of Scientific and Technical Information of China (English)

    Hai Yan Wang; Jian Jun Li; Xiao Na Cao; Ji Ying Xu; Mei Rong Liu; Yi Chen

    2012-01-01

    A surface plasmon resonance (SPR) method was presented to discriminate hemodialyzed T-lymphocytes from the normal based on antibody-cell recognition.By dynamic reaction with fixed anti-human CD4 antibody,SPR could offer significant signals to distinguish hemodialyzed patients from the healthy controls within 200 s after the cell injection in respect of either rising speed or maximum binding capacity (p < 0.01).The ratio method is also used to exclude the non-specific adsorption.The percentage of hemodialyzed patients' CD4+ T cells against the healthy control is 69 ± 18%.The most attractive of the present method is its ability to detect the intact and label-free lymphocytes,and further to detect the subpopulations,or proteins secreted by the desired lymphocytes subset.

  17. 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.

  18. CD4+ T-cell priming as biomarker to study immune response to preventive vaccines

    Directory of Open Access Journals (Sweden)

    Annalisa eCiabattini

    2013-12-01

    Full Text Available T-cell priming is a critical event in the initiation of the immune response to vaccination since it deeply influences both the magnitude and the quality of the immune response induced. CD4+ T-cell priming, required for the induction of high-affinity antibodies and immune memory, represents a key target for improving and modulating vaccine immunogenicity. A major challenge in the study of in vivo T-cell priming is due to the low frequency of antigen-specific T cells. This review discusses the current knowledge on antigen-specific CD4+ T-cell priming in the context of vaccination, as well as the most advanced tools for the characterization of the in vivo T-cell priming and the opportunities offered by the application of systems biology.

  19. Effect of Natalizumab on Circulating CD4(+) T-Cells in Multiple Sclerosis

    DEFF Research Database (Denmark)

    Börnsen, Lars; Christensen, Jeppe Romme; Ratzer, Rikke;

    2012-01-01

    In multiple sclerosis (MS), treatment with the monoclonal antibody natalizumab effectively reduces the formation of acute lesions in the central nervous system (CNS). Natalizumab binds the integrin very late antigen (VLA)-4, expressed on the surface of immune cells, and inhibits VLA-4 dependent......-cells due to reduced extravasation of activated and pro-inflammatory T-cells or due to induction of VLA-4 mediated co-stimulatory signals by natalizumab. In this study we examined how natalizumab treatment altered the distribution of effector and memory T-cell subsets in the blood compartment and if T......(HIGH) T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26(HIGH)CD4(+) T-cells in vitro. Otherwise CD4(+) T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. In conclusion natalizumab treatment selectively increased...

  20. 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...

  1. Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection.

    Science.gov (United States)

    Harari, Alexandre; Rizzardi, G Paolo; Ellefsen, Kim; Ciuffreda, Donatella; Champagne, Patrick; Bart, Pierre-Alexandre; Kaufmann, Daniel; Telenti, Amalio; Sahli, Roland; Tambussi, Giuseppe; Kaiser, Laurent; Lazzarin, Adriano; Perrin, Luc; Pantaleo, Giuseppe

    2002-08-15

    CD4 T-cell-specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1- and CMV-specific interferon-gamma-secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1-specific CD4 T-cell responses. A substantial proportion of CD4(+)CCR7(-) T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

  2. 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...

  3. 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.

  4. 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 is...

  5. Estimated average annual rate of change of CD4(+) T-cell counts in patients on combination antiretroviral therapy

    NARCIS (Netherlands)

    A. Mocroft; A.N. Phillips; B. Ledergerber; C. Smith; J.R. Bogner; K. Lacombe; A. Wiercinska-Drapalo; P. Reiss; O. Kirk; J.D. Lundgren

    2010-01-01

    Background: Patients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4(+) T-cell count according to levels of viraemia in patients on cART. Methods: A total of 111,371 CD4(+) T-cell counts and

  6. Down-regulation of promoter methylation level of CD4 gene after MDV infection in MD-susceptible chicken line

    Science.gov (United States)

    Marek’s disease virus (MDV) is an oncovirus that induces lymphoid tumors in susceptible chickens, and may affect the epigenetic stability of the CD4 gene. The purpose of this study was to find how the effect of MDV infection on DNA methylation status of the CD4 gene differed between MD-resistant (L6...

  7. 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;

    2001-01-01

    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...

  8. Absolute lymphocyte count is not a suitable alternative to CD4 count for determining initiation of antiretroviral therapy in fiji.

    Science.gov (United States)

    Balak, Dashika A; Bissell, Karen; Roseveare, Christine; Ram, Sharan; Devi, Rachel R; Graham, Stephen M

    2014-01-01

    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/mm(3). 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/mm(3) or 500 cells/mm(3). 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/mm(3) and if used as a surrogate for a CD4 of ≤500 cells/mm(3) 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.

  9. 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.

  10. The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis

    DEFF Research Database (Denmark)

    Krakowski, M L; Owens, T

    1997-01-01

    In experimental allergic encephalomyelitis (EAE), CD4+ T cells infiltrate the central nervous system (CNS). We derived CD4+ T cell lines from SJL/J mice that were specific for encephalitogenic myelin basic protein (MBP) peptides and produced both Th1 and Th2 cytokines. These lines transferred EAE...

  11. 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...

  12. 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...

  13. 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.

  14. 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...

  15. 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...

  16. 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

  17. 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.

  18. KI and WU polyomaviruses and CD4+ cell counts in HIV-1-infected patients, Italy.

    Science.gov (United States)

    Babakir-Mina, Muhammed; Ciccozzi, Massimo; Farchi, Francesca; Bergallo, Massimiliano; Cavallo, Rossana; Adorno, Gaspare; Perno, Carlo Federico; Ciotti, Marco

    2010-09-01

    To investigate an association between KI and WU polyomavirus (KIPyV and WUPyV) infections and CD4+ cell counts, we tested HIV-1-positive patients and blood donors. No association was found between cell counts and virus infections in HIV-1-positive patients. Frequency of KIPyV infection was similar for both groups. WUPyV was more frequent in HIV-1-positive patients.

  19. Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells.

    Science.gov (United States)

    Orent, William; Mchenry, Allison R; Rao, Deepak A; White, Charles; Klein, Hans-Ulrich; Bassil, Ribal; Srivastava, Gyan; Replogle, Joseph M; Raj, Towfique; Frangieh, Michael; Cimpean, Maria; Cuerdon, Nicole; Chibnik, Lori; Khoury, Samia J; Karlson, Elizabeth W; Brenner, Michael B; De Jager, Philip; Bradshaw, Elizabeth M; Elyaman, Wassim

    2016-01-15

    Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA. PMID:26604133

  20. 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...

  1. 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...

  2. 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 ...

  3. 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 ...

  4. 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+...

  5. 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...

  6. Dendritic Cells Enhance HIV Infection of Memory CD4(+) T Cells in Human Lymphoid Tissues.

    Science.gov (United States)

    Reyes-Rodriguez, Angel L; Reuter, Morgan A; McDonald, David

    2016-02-01

    Dendritic cells (DCs) play a key role in controlling infections by coordinating innate and adaptive immune responses to invading pathogens. Paradoxically, DCs can increase HIV-1 dissemination in vitro by binding and transferring infectious virions to CD4(+) T cells, a process called transinfection. Transinfection has been well characterized in cultured cell lines and circulating primary T cells, but it is unknown whether DCs enhance infection of CD4(+) T cells in vivo. In untreated HIV infection, massive CD4(+) T-cell infection and depletion occur in secondary lymphoid tissues long before decline is evident in the peripheral circulation. To study the role of DCs in HIV infection of lymphoid tissues, we utilized human tonsil tissues, cultured either as tissue blocks or as aggregate suspension cultures, in single-round infection experiments. In these experiments, addition of monocyte-derived DCs (MDDCs) to the cultures increased T-cell infection, particularly in CD4(+) T cells expressing lower levels of HLA-DR. Subset analysis demonstrated that MDDCs increased HIV-1 infection of central and effector memory T-cell populations. Depletion of endogenous myeloid DCs (myDCs) from the cultures decreased memory T-cell infection, and readdition of MDDCs restored infection to predepletion levels. Using an HIV-1 fusion assay, we found that MDDCs equally increased HIV delivery into naïve, central, and effector memory T cells in the cultures, whereas predepletion of myDCs reduced fusion into memory T cells. Together, these data suggest that resident myDCs facilitate memory T-cell infection in lymphoid tissues, implicating DC-mediated transinfection in driving HIV dissemination within these tissues in untreated HIV/AIDS.

  7. IL-6 Promotes Cardiac Graft Rejection Mediated by CD4+ Cells1

    OpenAIRE

    Booth, Adam Jared; Grabauskiene, Svetlana; Wood, Sherri Chan; Lu, Guanyi; Burrell, Bryna E.; Bishop, D. Keith

    2011-01-01

    IL-6 mediates numerous immunologic effects relevant to transplant rejection; however its specific contributions to these processes are not fully understood. To this end, we neutralized IL-6 in settings of acute cardiac allograft rejection associated with either CD8+ or CD4+ cell dominant responses. In a setting of CD8+ cell dominant graft rejection, IL-6 neutralization delayed the onset of acute rejection while decreasing graft infiltrate and inverting anti-graft Th1/Th2 priming dominance in ...

  8. 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...... in humans, and that the balance between subsets of parasite-specific T cells may play an important regulatory role in determining the outcome of the infections....

  9. 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

  10. The risk factors for suboptimal CD4 recovery in HIV infected population: an observational and retrospective study in Shanghai, China.

    Science.gov (United States)

    Zhang, Fengdi; Sun, Meiyan; Sun, Jianjun; Guan, Liqian; Wang, Jiangrong; Lu, Hongzhou

    2015-10-01

    Although the initiation of antiretroviral therapy (ART) has promoted the reconstitution of CD4+ T-cell count in the HIV infected population, not all patients can achieve the normalization of their immunologic functions. We analysed the variables associated with immunologic recovery, which is commonly regarded as the increase of CD4 to 350 cell/μL after a year of ART. We collected data from 3,485 patients attending a university-based HIV clinic from June 2005 to July 2014 in Shanghai, China. Logistic regression test was performed to analyse the risk factors for suboptimal CD4+ recovery following yearlong ART. The CD4+ T-cell of 723 participants (41.5% of the 1744 subjects) showed more than 350 cell/μL after one year of ART. Compared with baseline CD4 > 350 cell/μL, patients with baseline CD4 ≤ 200 cell/μL or 200 < CD4 ≤ 350 cell/μL were 42.6, 4.5 times more likely to be incomplete CD4 recovery, respectively. The risk of suboptimal immunologic recovery among patients with regimen including AZT or d4T were 2.1, 2.4 times higher compared with TDF, respectively. In our study, between optimal CD4 recovery group and suboptimal recovery group, there were no significant differences in age, gender, marital status, transmission routes, WHO stage, and CD4 recovery rates. As for the dynamic CD4 change, we found the CD4 recovery rates were 49.9% and 61.8% in the second and third year of ART, respectively. Patients who had a low level of CD4+ T-cell count (< 200 cell/μL) during the initiation of ART exhibited more difficulties recovering to a normal level. Furthermore, the regimen, including AZT or d4T, was not beneficial to CD4 recovery. So, more efforts should be made to guarantee the early diagnosis and timely treatment for HIV/AIDS patients, and simultaneously optimize antiretroviral therapy. PMID:26559026

  11. CD4 on CD8+ T cells directly enhances effector function and is a target for HIV infection

    Science.gov (United States)

    Kitchen, Scott G.; Jones, Nicole R.; Laforge, Stuart; Whitmire, Jason K.; Vu, Bien-Aimee; Galic, Zoran; Brooks, David G.; Brown, Stephen J.; Kitchen, Christina M. R.; Zack, Jerome A.

    2004-06-01

    Costimulation of purified CD8+ T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8+ T cell function by modulating expression of IFN- and Fas ligand, two important CD8+ T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-, Fas ligand, and the cytotoxic responses of activated CD8+ T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease.

  12. 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.

  13. 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

  14. Human CD4+ T cell epitopes from vaccinia virus induced by vaccination or infection.

    Directory of Open Access Journals (Sweden)

    J Mauricio Calvo-Calle

    2007-10-01

    Full Text Available Despite the importance of vaccinia virus in basic and applied immunology, our knowledge of the human immune response directed against this virus is very limited. CD4(+ T cell responses are an important component of immunity induced by current vaccinia-based vaccines, and likely will be required for new subunit vaccine approaches, but to date vaccinia-specific CD4(+ T cell responses have been poorly characterized, and CD4(+ T cell epitopes have been reported only recently. Classical approaches used to identify T cell epitopes are not practical for large genomes like vaccinia. We developed and validated a highly efficient computational approach that combines prediction of class II MHC-peptide binding activity with prediction of antigen processing and presentation. Using this approach and screening only 36 peptides, we identified 25 epitopes recognized by T cells from vaccinia-immune individuals. Although the predictions were made for HLA-DR1, eight of the peptides were recognized by donors of multiple haplotypes. T cell responses were observed in samples of peripheral blood obtained many years after primary vaccination, and were amplified after booster immunization. Peptides recognized by multiple donors are highly conserved across the poxvirus family, including variola, the causative agent of smallpox, and may be useful in development of a new generation of smallpox vaccines and in the analysis of the immune response elicited to vaccinia virus. Moreover, the epitope identification approach developed here should find application to other large-genome pathogens.

  15. Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema.

    Science.gov (United States)

    Ogata, Fusa; Fujiu, Katsuhito; Matsumoto, Sahohime; Nakayama, Yukiteru; Shibata, Munehiko; Oike, Yuichi; Koshima, Isao; Watabe, Tetsuro; Nagai, Ryozo; Manabe, Ichiro

    2016-03-01

    Lymphedema is a debilitating progressive condition that severely restricts quality of life and is frequently observed after cancer surgery. The mechanism underlying lymphedema development remains poorly understood, and no effective pharmacological means to prevent or alleviate the ailment is currently available. Using a mouse model of lymphedema, we show here that excessive generation of immature lymphatic vessels is essential for initial edema development and that this early process is also important for later development of lymphedema pathology. We found that CD4(+) T cells interact with macrophages to promote lymphangiogenesis, and that both lymphangiogenesis and edema were greatly reduced in macrophage-depleted mice, lymphocyte-deficient Rag2(?/?) mice or CD4(+) T-cell-deficient mice. Mechanistically, T helper type 1 and T helper type 17 cells activate lesional macrophages to produce vascular endothelial growth factor-C, which promotes lymphangiogenesis, and inhibition of this mechanism suppressed not only early lymphangiogenesis, but also later development of lymphedema. Finally, we show that atorvastatin suppresses excessive lymphangiogenesis and lymphedema by inhibiting T helper type 1 and T helper type 17 cell activation. These results demonstrate that the interaction between CD4(+) T cells and macrophages is a potential therapeutic target for prevention of lymphedema after surgery.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 安阳市HIV感染者和患者CD+4T淋巴细胞检测分析%Analysis on Testing Results of CD+4T Lymphocyte among HIV Infectors and AIDS Patients in Anyang City

    Institute of Scientific and Technical Information of China (English)

    张相萍; 胡秀杰

    2011-01-01

    目的 检测安阳地区可随访到的56例HIV感染者和患者(HIV和AIDS)的CD+4T淋巴细胞值,分析CD+4、CD+8T淋巴细胞水平,以了解HIV和AIDS病程进展情况,为抗病毒治疗提供依据.方法 对56份抗凝血标本通过BD FACSCount流式细胞仪进行CD+4和CD+8 T淋巴细胞绝对值及CD+4/CD+8比值的检测,统计分析测定值.结果 检测56份样本中,CD+4T淋巴细胞绝对计数(第2版)标准,安阳市能随访到的HIV感染者已经进入发病高峰.%[Objective]To test the CD4+T Lymphocyte of 56 HIV infectors and AIDS patients in Anyang Area, to analyze their CD4+, CD8+ T lymphocyte levels so as to understand the progression of HIV and AIDS cases, and provide evidence for antiviral therapy. [ Methods ] BD FACS count flow cytometry was adopted to test the absolute value of lymphocyte of CD4+, CD8+ T lymphocyte,and the ratio of CD4+/CD8+ of 56 anticoagulant specimens collected from HIV infectors and AIDS patients. The results were analyzed.[Results]Of 56 specimens, 32 specimens' CD4+ T lymphocyte counts < 200/μl 200/ul, accounting for 57. 14%; 12 specimens'CD4+ T lymphocyte counts were between 200 - 300/ul, accounting for 21.43 %; 8 examples' CD4+ T lymphocyte counts were 300 -500/ul, accounting for 14.29 %. There were 96.43% specimens whose ratio of CD4+/CD8+ < 1.[ Conclusion ] According to the criterion of the “ National Free AIDS Antivirotic Medicine Treatment Handbook” (the second edition), HIV Infectors who could be followed in Anyang City has reached the peak of onset.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. Isolation and Ex Vivo Culture of Vδ1+CD4+γδ T Cells, an Extrathymic αβT-cell Progenitor.

    Science.gov (United States)

    Welker, Christian; Handgretinger, Rupert; Schilbach, Karin

    2015-12-07

    The thymus, the primary organ for the generation of αβ T cells and backbone of the adaptive immune system in vertebrates, has long been considered as the only source of αβT cells. Yet, thymic involution begins early in life leading to a drastically reduced output of naïve αβT cells into the periphery. Nevertheless, even centenarians can build immunity against newly acquired pathogens. Recent research suggests extrathymic αβT cell development, however our understanding of pathways that may compensate for thymic loss of function are still rudimental. γδ T cells are innate lymphocytes that constitute the main T-cell subset in the tissues. We recently ascribed a so far unappreciated outstanding function to a γδ T cell subset by showing that the scarce entity of CD4(+) Vδ1(+)γδ T cells can transdifferentiate into αβT cells in inflammatory conditions. Here, we provide the protocol for the isolation of this progenitor from peripheral blood and its subsequent cultivation. Vδ1 cells are positively enriched from PBMCs of healthy human donors using magnetic beads, followed by a second step wherein we target the scarce fraction of CD4(+) cells with a further magnetic labeling technique. The magnetic force of the second labeling exceeds the one of the first magnetic label, and thus allows the efficient, quantitative and specific positive isolation of the population of interest. We then introduce the technique and culture condition required for cloning and efficiently expanding the cells and for identification of the generated clones by FACS analysis. Thus, we provide a detailed protocol for the purification, culture and ex vivo expansion of CD4(+) Vδ1(+)γδ T cells. This knowledge is prerequisite for studies that relate to this αβT cell progenitor`s biology and for those who aim to identify the molecular triggers that are involved in its transdifferentiation.

  11. 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.

  12. Idiopathic CD4+ lymphocytopenia in Hispanic male: case report and literature review

    Directory of Open Access Journals (Sweden)

    Said S

    2014-07-01

    Full Text Available Sarmad Said,1 Haider Alkhateeb,1 Chad J Cooper,1 Emmanuel Rodriguez,1 Remi Trien,1 German T Hernandez,1,2 Hasan S Salameh1,2 1Department of Internal Medicine, 2Department of Internal Medicine, Division of Nephrology and Hypertension, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, USA Introduction: Idiopathic cluster of differentiation 4 (CD4+ T-cell lymphocytopenia (ICL is a rare non human immunodeficiency virus (HIV-related syndrome with unclear natural history and prognosis that was first reported and defined in 1992. ICL has been observed in patients after the onset of an opportunistic infection without known immunosuppression. Case presentation: A 20-year-old Hispanic male patient without significant past medical history presented with progressive shortness of breath and cough for 3 weeks. Chest computed tomography showed bilateral cavitary lesions in the upper lung lobes. The HIV rapid screening test as well as the sputum acid-fast bacilli test were both positive. The patient was started on antituberculosis therapy. The CD4 count was noticed to be low. However, the HIV Western blot test was negative, and the HIV viral load was within normal limit. Further radiologic studies, hemato-oncologic, and autoimmune workups were normal. The patient was discharged on the treatment for tuberculosis. Follow-up after 8 weeks revealed a persistent low CD4+ count, and the repeated HIV tests were negative. Conclusion: The clinical features of ICL range from an asymptomatic condition to life-threatening complications that imitate the clinical course of HIV-infected patients. The differential diagnosis in adults comprises primarily HIV infection and other diseases or drug side effects. ICL is very rare and should be considered in the absence of any defined immunodeficiency or therapy associated with depressed levels of CD4+ T-cells. Early detection and recognition of the disease allow purposeful and

  13. 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.

  14. 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.

  15. 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.

  16. 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...

  17. 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.

  18. 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...

  19. 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.

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

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    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.

  1. 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

  2. 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.

  3. PD-1/PD-Ls pathways between CD4(+) T cells and pleural mesothelial cells in human tuberculous pleurisy.

    Science.gov (United States)

    Yin, Wen; Tong, Zhao-Hui; Cui, Ai; Zhang, Jian-Chu; Ye, Zhi-Jian; Yuan, Ming-Li; Zhou, Qiong; Shi, Huan-Zhong

    2014-03-01

    Programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and PD-L2 have been demonstrated to be involved in tuberculosis immunity, however, the expression and regulation of PD-1/PD-Ls pathways in pleural mesothelial cells (PMCs) and CD4(+) T cells in tuberculous pleural effusion (TPE) have not been investigated. Expression of PD-1 on CD4(+) T cells and expressions of PD-L1 and PD-L2 on PMCs in TPE were determined. The impacts of PD-1/PD-Ls pathways on proliferation, apoptosis, adhesion, and migration of CD4(+) T cells were explored. Concentrations of soluble PD-l, but not of soluble PD-Ls, were much higher in TPE than in serum. Expressions of PD-1 on CD4(+) T cells in TPE were significantly higher than those in blood. Expressions of PD-Ls were much higher on PMCs from TPE when compared with those from transudative effusion. Interferon-γ not only upregulated the expression of PD-1 on CD4(+) T cells, but also upregulated the expressions of PD-Ls on PMCs. Blockage PD-1/PD-Ls pathways abolished the inhibitory effects on proliferation and adhesion activity of CD4(+) T cells induced by PMCs. PD-1/PD-Ls pathways on PMCs inhibited proliferation and adhesion activity of CD4(+) T cells, suggesting that Mycobacterium tuberculosis might exploit PD-1/PD-Ls pathways to evade host cell immune response in human.

  4. 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;

    2013-01-01

    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...... 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...

  5. Single Particle Tracking reveals two distinct environments for CD4 receptors at the surface of living T lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Mascalchi, Patrice; Lamort, Anne Sophie; Salome, Laurence [CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse (France); Universite de Toulouse, UPS, IPBS (Institut de Pharmacologie et de Biologie Structurale), F-31077 Toulouse (France); Dumas, Fabrice, E-mail: fabrice.dumas@ipbs.fr [CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse (France); Universite de Toulouse, UPS, IPBS (Institut de Pharmacologie et de Biologie Structurale), F-31077 Toulouse (France)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer We studied the diffusion of single CD4 receptors on living lymphocytes. Black-Right-Pointing-Pointer This study reveals that CD4 receptors have either a random or confined diffusion. Black-Right-Pointing-Pointer The dynamics of unconfined CD4 receptors was accelerated by a temperature raise. Black-Right-Pointing-Pointer The dynamics of confined CD4 receptors was unchanged by a temperature raise. Black-Right-Pointing-Pointer Our results suggest the existence of two different environments for CD4 receptors. -- Abstract: We investigated the lateral diffusion of the HIV receptor CD4 at the surface of T lymphocytes at 20 Degree-Sign C and 37 Degree-Sign C by Single Particle Tracking using Quantum Dots. We found that the receptors presented two major distinct behaviors that were not equally affected by temperature changes. About half of the receptors showed a random diffusion with a diffusion coefficient increasing upon raising the temperature. The other half of the receptors was permanently or transiently confined with unchanged dynamics on raising the temperature. These observations suggest that two distinct subpopulations of CD4 receptors with different environments are present at the surface of living T lymphocytes.

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

    DEFF Research Database (Denmark)

    Jensen, Helle; Folkersen, Lasse; Skov, Søren

    2012-01-01

    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......NKG2D is a stimulatory receptor expressed by natural killer (NK) cells, CD8(+) T-cells, and ¿d 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...

  7. 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

  8. 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.

  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. Functional maturation of mouse CD4~+CD8~- thymocytes induced by medullary-type thymus epithelial cells

    Institute of Scientific and Technical Information of China (English)

    路力生; 陈慰峰

    1996-01-01

    Murine CD4+CD8- (CD4SP) thymocyte subset is a heterogeneous population, in which the Qa-2- cells are less functional, whereas the Qa-2+ cells are fully functional. Evidence is provided here that the transition from Qa-2- to Qa-2+ CD4SP thymocytes is an intrathymic process of differentiation induced by thymic medullary-type epithelial cells. The separated Qa-2-CD4SP could be induced to express Qa-2 molecules up to 84%- 89% of the total viable celb after cocultured for 3d with MTEC1 cells, a murine thymic medullary type epithelial cell line established in our laboratory. Kinetic study showed that both the percentage of Qa-2+ cells and the density of the expressed Qa-2 molecules on CD4SP thymocytes induced by MTEC1 were progressively increasing in 72-h cultures. The MTECl-induced Qa-2+CD4SP thymocytes were fully functional, which exhibited capabilities of proliferation and cytokine secretion in response to Con A stimulation as high as those of freshly isolated Qa-2+CD4SP thymocytes. The profile of cytokine

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

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    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.

  12. CD4 eligibility thresholds: an analysis of the time to antiretroviral treatment in West African HIV-1 seroconverters

    Science.gov (United States)

    Minga, Albert; Lewden, Charlotte; Gabillard, Delphine; Bomisso, Germain; Toni, Thomas-d’Aquin; Emième, Arlette; Yapo, Vincent; Inwoley, André; Salamon, Roger; Anglaret, Xavier

    2013-01-01

    Background WHO recommends initiating combination antiretroviral treatment (ART) at the minimal threshold of 350 CD4 cells/mm3. In sub-Saharan Africa, the time for a recently infected patient to reach this threshold is unclear. Method We estimated the probability of reaching different CD4 thresholds over time in the ANRS 1220 cohort of HIV-1 seroconverters in Côte d’Ivoire. CD4 slopes were estimated using a mixed linear model. Probabilities of crossing the 350 and 500 CD4 cells/mm3 thresholds were estimated by the Kaplan-Meier method. Results Between 1997 and 2009, 304 recent seroconverters have been enrolled in the Primo-CI cohort (62% men, median baseline age 29 years, median time since the estimated date of seroconversion 9 months). The probability of having a first CD4 count below 500/mm3 was 0.57, 0.72, 0.79 and 0.84 at study entry, 2, 4 and 6 years, respectively. For a first CD4 count below 350/mm3, these figures were 0.29, 0.40, 0.55 and 0.67. The time for 75% of patients to reach the threshold was 3.0 years for 500 CD4/mm3 and 7.0 years for 350 CD4/mm3. Conclusion Almost one third of recent seroconverters had a CD4 count below the current ART eligibility threshold at first contact, about 6% more crossed it each subsequent year, and 25% remained above this threshold after 7 years. If the threshold was raised to 500 cells/mm3, 57% of recent seroconverters would immediately be eligible, while 14% would remain above the threshold at 7 years. These results should help modelers and treatment providers anticipate the need in antiretroviral drugs. PMID:21412060

  13. CD4(+)B220(+)TCRγδ(+) T cells produce IL-17 in lupus-prone MRL/lpr mice.

    Science.gov (United States)

    Qiu, Feng; Li, Tingting; Zhang, Kui; Wan, Jun; Qi, Xiaokun

    2016-09-01

    Systemic lupus erythematosus is an autoimmune disease with comprehensive immune cell disorders. Recent studies suggested that pro-inflammatory cytokine IL-17 plays important role in lupus, leaving the cellular sources and their pathogenic and physiologic characters largely unknown. In the current study, by using lupus-prone MRL/lpr mice, we demonstrated that Th17 response prevails in lupus disease regarding significantly accumulated serum IL-17, increased IL-17-producing splenocytes, and elevated phospho-STAT3 in CD4(+) T cells. Intracellular staining revealed that unusual CD4(+)B220(+) T cells are major IL-17-producing cells, whereas conventional CD4(+)B220(-) T cells are major IFN-γ-producing cells. Subsequent studies showed that CD4(+)B220(+) cells contains both αβ and γδ T cells in the spleen and thymus of MRL/lpr mice. Further study showed that around 60% of γδ T cells in MRL/lpr mice co-express both B220 and CD4 on their surface, and are the major RORγt(+) cells in MRL/lpr mice. Finally, CD4(+)B220(+) T cells alone do not proliferate, but could enhance the proliferation and IFN-γ-production of conventional CD4(+)B220(-) T cells. Our findings suggest the pathogenic role of unusual CD4(+)B220(+) T cells in lupus disease in MRL/lpr mice according to their IL-17-producing ability and stimulatory function for conventional CD4(+)B220(-) T cells. PMID:27235595

  14. 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.

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

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    Fengliang Liu

    2016-06-01

    Full Text Available 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.

  16. Identification of CD4-Binding Site Dependent Plasma Neutralizing Antibodies in an HIV-1 Infected Indian Individual.

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    Lubina Khan

    Full Text Available Dissecting antibody specificities in the plasma of HIV-1 infected individuals that develop broadly neutralizing antibodies (bNAbs is likely to provide useful information for refining target epitopes for vaccine design. Several studies have reported CD4-binding site (CD4bs antibodies as neutralization determinants in the plasma of subtype B-infected individuals; however there is little information on the prevalence of CD4bs specificities in HIV-infected individuals in India. Here, we report on the presence of CD4bs antibodies and their contribution to virus neutralization in the plasma from a cohort of HIV-1 infected Indian individuals. Plasma from 11 of the 140 HIV-1 infected individuals (7.9% studied here exhibited cross-neutralization activity against a panel of subtype B and C viruses. Analyses of these 11 plasma samples for the presence of CD4bs antibodies using two CD4bs-selective probes (antigenically resurfaced HXB2gp120 core protein RSC3 and hyperglycosylated JRFLgp120 mutant ΔN2mCHO revealed that five (AIIMS 617, 619, 627, 642, 660 contained RSC3-reactive plasma antibodies and only one (AIIMS 660 contained ΔN2mCHO-reactive antibodies. Plasma antibody depletion and competition experiments confirmed that the neutralizing activity in the AIIMS 660 plasma was dependent on CD4bs antibodies. To the best of our knowledge, this is the first study to report specifically on the presence of CD4bs antibodies in the plasma of a cohort of HIV-1 infected Indian donors. The identification of CD4bs dependent neutralizing antibodies in an HIV-1 infected Indian donor is a salient finding of this study and is supportive of ongoing efforts to induce similar antibodies by immunization.

  17. 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

  18. Impact of long-term viral suppression in CD4+ recovery of HIV-children on Highly Active Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    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. 凉山州2011年艾滋病病例CD4细胞检测情况分析%Analysis of the CD4 testing of HIV/AIDS cases in Liangshan Prefecture in 2011

    Institute of Scientific and Technical Information of China (English)

    黑发欣; 龚煜汉; 李崇行; 边仕超; 马兆瑾; 李洋亚; 王亮; 刘鹏; 刘中夫

    2013-01-01

    Objective To analyze CD4 testing of HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) cases in Liangshan Prefecture in 2011, and to provide scientific evidence for the improvement of the quality of work and funding efficiency. Methods Data were collected about CD4 testing of HIV / AIDS follow-up cases in Liangshan Prefecture in 2011 from "Chinese National Comprehensive HIV/AIDS Prevention and Care Information System", and were analyzed in accordance with the status of case survived and disease development. Results The proportion of CD4 testing of HIV/AIDS follow-up cases in Liangshan Prefecture in 2011 was 55. 8%. The number of CD4 testing increased by 56. 5% compared to that in 2010. The proportion of one CD4 test completion in the survived HIV cases was 49. 2%, and that of two CD4 tests in the survived AIDS cases was 58. 5%; the proportion of completing two CD4 tests in untreated AIDS cases was 31. 6%; the proportion of completing two CD4 tests among treated AIDS cases was 93. 0%; the proportion of CD4 testing of deceased HIV cases was 8. 1% ; the proportion of CD4 testing of deceased AIDS cases was 44. 0%. Repeated CD4 testing accounted for 20. 2% of the total annual testing number. The coverage of antiretroviral treatment of HIV/AIDS cases with CD4 less than 350/mm3 was 64. 9%. Conclusion CD4 testing of HIV/ AIDS cases in Liangshan Prefecture achieved remarkable outcome, detection number grow rapidly, completion rate of CD4 testing of treated AIDS cases exceeds 23. 0% of the national evaluation standard. However, repeated and unnecessary detection should be avoided, detection rate should be improved further and treatment coverage should be enlarged.%目的 分析2011年凉山州艾滋病病毒(HIV)感染者/艾滋病(AIDS)病人(简称HIV/AIDS病例)的CD4细胞检测情况,为提高工作质量及经费使用效益提供科学依据.方法 在“艾滋病综合防治数据信息管理系统”中下载2011年凉山州的历史卡片,

  20. 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...

  1. 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...

  2. 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...

  3. The Effect of Low CD4+ Lymphocyte Count on the Radiographic Patterns of HIV Patients with Pulmonary Tuberculosis among Nigerians.

    Science.gov (United States)

    Affusim, Christopher; Abah, Vivien; Kesieme, Emeka B; Anyanwu, Kester; Salami, Taofik A T; Eifediyi, Reuben

    2013-01-01

    Objective. To assess the radiographic features in patients with Human Immunodeficiency Virus (HIV) complicated by pulmonary tuberculosis (PTB), and the association with CD4 lymphocyte count and sputum smear. Method. A prospective study was carried out on 89 HIV positive patients with PTB. The demographics, smoking history, sputum smear result, chest radiographic findings and CD4 lymphocyte count were documented. Results. Out of the 89 patients recruited in the study, 41 were males and 48 were females. Eighteen (18) patients had typical radiographic features, 60 patients had atypical radiographic features while only 11 of them had normal radiographic films. Sixty eight (68) patients had CD4 count HIV) complicated by pulmonary tuberculosis.

  4. 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...

  5. 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

  6. 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

  7. Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys1

    OpenAIRE

    Gordon, Shari N.; Klatt, Nichole R.; Bosinger, Steven E; Brenchley, Jason M.; Milush, Jeffrey M.; Engram, Jessica C.; Dunham, Richard M.; Paiardini, Mirko; Klucking, Sara; Danesh, Ali; Strobert, Elizabeth A.; Apetrei, Cristian; Pandrea, Ivona V.; Kelvin, David; Douek, Daniel C.

    2007-01-01

    HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs i...

  8. Estimated average annual rate of change of CD4(+) T-cell counts in patients on combination antiretroviral therapy

    DEFF Research Database (Denmark)

    Mocroft, Amanda; Phillips, Andrew N; Ledergerber, Bruno;

    2010-01-01

    and viral load measurements in 8,227 patients were analysed. Annual change in CD4(+) T-cell numbers was estimated using mixed models. RESULTS: After adjustment, the estimated average annual change in CD4(+) T-cell count significantly increased when viral load was ... was >/=10,000 copies/ml (-44.4 cells/mm(3), 95% CI -62.0--26.9; P=0.0012, test for interaction). CONCLUSIONS: On average, CD4(+) T-cell counts did not significantly decrease until the viral load exceeded 10,000 copies/ml in patients treated with a boosted PI-containing cART regimen, but decreased...

  9. Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35.

    Science.gov (United States)

    Bardel, Emilie; Larousserie, Frédérique; Charlot-Rabiega, Pascaline; Coulomb-L'Herminé, Aurore; Devergne, Odile

    2008-11-15

    EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3(+) nor CD25(+) cells coexpressed EBI3. Similarly, Foxp3(+) cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4(+) T cells, CD8(+) and gammadelta T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8(+) and gammadelta T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4(+) T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35.

  10. Application of "CD-4" Theory for Determining the Width of Implant in Breast Augmentation

    Institute of Scientific and Technical Information of China (English)

    Jie Cai; Yang Zhou

    2015-01-01

    Background:The determination of the width of the implant is the first key step to select shape and volume of the implant in breast augmentation.The aim of this study was to introduce a new method to determine the width of the implant (W) and explain the reasons to do so in details.Methods:From January 2006 to June 2014,the authors have found and applied "CD-4" theory to determine the width of breast implant (W) in dual plane Ⅰ or Ⅱ breast augmentation cases through transaxillary or periareolar incision for 560 patients."CD" is defined as the curved distance on skin from the midline of the sternal bone to the anterior axillary line (AAL) on the lateral chest wall through the horizontal level on inferior mammary fold.W =CD-4 (or 3.5) cm.Results:The 560 patients used both round and anatomic implants with W from 10.5 cm to 12.5 cm.Their CDs are from 14.5 cm to 17 cm.About 78% of the patients have got followed up from 1 month to 5 years postoperatively.Except for four patients who got unilateral capsular contractions,all the other patients are satisfied with their nature new breast shapes and volumes.Their new intermammary cleavages without bras are between 1 cm and 2.5 cm,and lateral borders of the breast are on the area of the AAL.Conclusions:W (width of the implant) =CD-4 (cm) when doing dual plan Ⅰ or Ⅱ breast augmentation.For the very thin patient,4 should be 3.5.

  11. 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.

  12. Circulating subsets and CD4(+)CD25(+) regulatory T cell function in chronic inflammatory demyelinating polyradiculoneuropathy.

    Science.gov (United States)

    Sanvito, Lara; Makowska, Anna; Gregson, Norman; Nemni, Raffaello; Hughes, Richard A C

    2009-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory disease of the peripheral nervous system that is probably autoimmune in origin. Different components of the adaptive and innate immunity may be responsible for the aberrant response towards nerve antigens. To investigate this, we examined lymphocyte subsets and regulatory T cell (Treg) function in the blood of CIDP patients, healthy controls (HC) and subjects with non-immune mediated neuropathies (other neuropathies, ON). We used flow cytometry to determine the frequency of monocytes, B cells, natural killer (NK) and NK-T cells, total and activated CD4(+) and CD8(+) T cells, effector memory and central memory CD4(+) and CD8(+) T cells, and CD4(+)CD25(high)Foxp3(+) Tregs. Treg function was studied after polyclonal stimulation and antigen specific stimulation with myelin protein peptides in CIDP and HC. There was an increased frequency of monocytes (p = 0.02) and decreased frequency of NK cells (p = 0.02) in CIDP compared with HC but not ON. There were no significant differences in other populations. Treg function was impaired in CIDP compared to HC (p = 0.02), whilst T cell proliferation to myelin protein peptides before and after depletion of Tregs was not different between patients and controls. This study shows increased circulating monocytes and reduced NK cells in CIDP. Although Treg frequency was not altered, we confirm that Tregs display a defect of suppressive function. Myelin protein peptides were not the target of the altered peripheral regulation of the immune response. The mechanisms of peripheral immune tolerance in CIDP and their relevance to the pathogenesis deserve further exploration.

  13. 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.

  14. CD4 count levels and pattern of respiratory complications in HIV seropositive patients in Calabar, Nigeria.

    Science.gov (United States)

    Peters, E J; Essien, O E; Immananagha, K K; Inah, G A; Philip-Ephraim, E E; Agbulu, R E

    2007-01-01

    A prospective observational study was carried out to describe the pattern of pulmonary complications in hospitalized patients with Human Immune-deficiency Virus (HIV) infection at the University of Calabar Teaching Hospital, Calabar between January 2005 to December 2006. One hundred and twenty-four patients which consists 60 males and 64 females, aged between 20-60 who met the inclusion criteria formed the subjects for the study. The mean age of the subjects was 34.60 +/-1.2 years. A structured questionnaire was used to obtain the demographic data, clinical information and CD4 lymphocyte count. Radiological analysis of chest was done with the chest X-ray of each subject. Chronic productive cough topped the list of respiratory symptoms (89%) followed by chest pain (74%) and dyspnea (62 %). Lung consolidation was the commonest respiratory sign as seen in 44 % of the cases. Hilar lymphadenopathy was seen in (35 %), Pleural effusion (32%), lung fibrosis (21%) and finger clubbing (15%). The clinical and radiological pattern of most patients with chronic cough was highly suggestive of mycobacterial infection such as tuberculosis, although only 40% of cases had positive acid fast bacilli. The mean CD4 lymphocyte count level was 174.8 +/- 5.4 cells/microlitre and this may be responsible for the respiratory findings as opportunistic lung infections are said to be commoner at CD4 count levels below 200 cells/microlitre. However, four patients had mediasternal masses which may suggest neoplasms. Concerted efforts and continuous evaluation of these patients are needed to determine the spectrum of respiratory illnesses among HIV positive patients in Calabar.

  15. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up

    DEFF Research Database (Denmark)

    Lundgren, Jens; Babiker, Abdel; El-Sadr, Wafaa;

    2008-01-01

    BACKGROUND AND METHODS: The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease...... or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported. RESULTS: During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count ...%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count

  16. Predictors of CD4 count change over 8 months of follow up in HIV-1-infected patients with a CD4 count>or=300 cells/microL who were assigned to 7.5 MIU interleukin-2

    DEFF Research Database (Denmark)

    Fox, Zoe; Antunes, Francisco; Davey, Rick;

    2007-01-01

    -1-positive individuals. The IL-2 induction phase consists of three dosing cycles over 6-8 months (7.5 MIU twice a day, for 5 days every 8 weeks). METHODS: We included patients initiating IL-2 at the 7.5 MIU dose with an 8-month CD4 count, measured at least 30 days after their last cycle. We...... identified baseline predictors of CD4 count changes over 8 months using linear regression. RESULTS: Of 2090 patients assigned IL-2, 1673 (80%) were included in the analysis. The median (interquartile range) baseline CD4 count was 461 (370, 587) cells/microL with a median increase of 233 (90, 411) cells...... in the first cycle and CD4 count change (73.1 cells/microL greater increase per 15 MIU higher; Pindividuals...

  17. 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.

  18. Functional signatures of human CD4 and CD8 T cell responses to Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Teresa ePrezzemolo

    2014-04-01

    Full Text Available With 1.4 million deaths and 8.7 million new cases in 2011, tuberculosis (TB remains a global health care problem and together with HIV and Malaria represents the one of the three infectious diseases world-wild. Control of the global TB epidemic has been impaired by the lack of an effective vaccine, by the emergence of drug-resistant forms of Mycobacterium tuberculosis (Mtb and by the lack of sensitive and rapid diagnostics. It is estimated, by epidemiological reports, that one third of the world’s population is latently infected with Mtb, but the majority of infected individuals develops long-lived protective immunity, which controls and contains Mtb in a T cell-dependent manner. Development of TB disease results from interactions among the environment, the host, and the pathogen, and known risk factors include HIV coinfection, immunodeficiency, diabetes mellitus, overcrowding, malnutrition, and general poverty; therefore an effective T cell response determines whether the infection resolves or develops into clinically evident disease. Consequently, there is great interest in determining which T cells subsets mediate anti-mycobacterial immunity, delineating their effector functions. On the other hand, many aspects remain unsolved in understanding why some individuals are protected from Mtb infection while others go on to develop disease.Several studies have demonstrated that CD4+ T cells are involved in protection against Mtb, as supported by the evidence that CD4+ T cell depletion is responsible for Mtb reactivation in HIV-infected individuals. There are many subsets of CD4+ T cells, such as T-helper 1 (Th1, Th2, Th17, and regulatory T cells (Tregs, and all these subsets cooperate or interfere with each other to control infection; the dominant subset may differ between active and latent Mtb infection cases. Mtb-specific CD4+ Th1 cell response is considered to have a protective role for the ability to produce cytokines such as IFN- or TNF

  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. 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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.

  6. 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.

  7. Statins disrupt CCR5 and RANTES expression levels in CD4(+ T lymphocytes in vitro and preferentially decrease infection of R5 versus X4 HIV-1.

    Directory of Open Access Journals (Sweden)

    Alexey A Nabatov

    Full Text Available BACKGROUND: Statins have previously been shown to reduce the in vitro infection of human immunodeficiency virus type 1 (HIV-1 through modulation of Rho GTPase activity and lipid raft formation at the cell surface, as well as by disrupting LFA-1 incorporation into viral particles. PRINCIPLE FINDINGS: Here we demonstrate that treatment of an enriched CD4(+ lymphocyte population with lovastatin (Lov, mevastatin (Mev and simvastatin (activated and non-activated, Sim(A and Sim(N, respectively can reduce the cell surface expression of the CC-chemokine receptor CCR5 (P<0.01 for Sim(A and Lov. The lowered CCR5 expression was associated with down-regulation of CCR5 mRNA expression. The CC-chemokine RANTES protein and mRNA expression levels were slightly increased in CD4(+ enriched lymphocytes treated with statins. Both R5 and X4 HIV-1 were reduced for their infection of statin-treated cells; however, in cultures where statins were removed and where a decrease in CCR5 expression was observed, there was a preferential inhibition of infection with an R5 versus X4 virus. CONCLUSIONS: The results indicate that the modulation of CC-chemokine receptor (CCR5 and CC-chemokine (RANTES expression levels should be considered as contributing to the anti-viral effects of statins, preferentially inhibiting R5 viruses. This observation, in combination with the immunomodulatory activity exerted by statins, suggests they may possess more potent anti-HIV-1 activity when applied during the early stages of infection or in lowering viral transmission. Alternatively, statin treatment could be considered as a way to modulate immune induction such as during vaccination protocols.

  8. 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

  9. 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;

    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...

  10. Detection of CD4+ and CD8 + T-lymphocytes with the optofluidic ring resonator (OFRR) biosensor

    Science.gov (United States)

    Gohring, John T.; Fan, Xudong

    2009-05-01

    We have demonstrated the use of the Opto-Fluidic ring resonator (OFRR) to achieve the label-free detection of CD4+ and CD8+ T-Lymphocytes. The OFRR sensing technology combines microfluidics and optical sensing in a small platform that achieves rapid detection. In this work, white blood cells were obtained from healthy blood and the concentration altered to reflect CD4 and CD8 concentrations of HIV infected individuals. The OFRR was modified to effectively capture these receptors located on T-Lymphocytes and obtain a sensing signal through interaction with an evanescent field. Results show isolation of CD4+ and CD8+ T-Lymphocytes at medically significant levels. This work will lead to a device that can provide a CD4 and CD8 count to measure HIV progression in a low cost sensing setup.

  11. Correlation analysis on total lymphocyte count and CD4 count in HIV-infected patients: a retrospective evaluation.

    Science.gov (United States)

    Wang, Yuming; Liang, Shuying; Yu, Erman; Guo, Jinling; Li, Zizhao; Wang, Zhe; Du, Yukai

    2011-10-01

    CD4 count is the standard method for determining eligibility for highly active antiretroviral therapy (HAART) and monitoring HIV/AIDS disease progression, but it is not widely available in resource-limited settings. This study examined the correlation between total lymphocyte count (TLC) and CD4 count of HIV-infected patients before and after HAART, and assessed the thresholds of TLC for making decisions about the initiation and for monitoring HAART. A retrospective study was performed, and 665 HIV-infected patients with TLC and CD4 count from four counties (Shangcai, Queshan, Shenqiu and Weishi) were included in the study. Pearson correlation and receiver operating characteristic (ROC) were used. TLC and CD4 count after HAART was significantly increased as compared with pre-HAART (PHIV-infected individuals for making decisions about the initiation and for monitoring HAART in resource-limited settings.

  12. Prevalence of Oral Manifestations and Their Association with CD4/CD8 Ratio and HIV Viral Load in South India

    Directory of Open Access Journals (Sweden)

    Sharma Gaurav

    2011-01-01

    Full Text Available The objective of the present research was to determine the prevalence of oral manifestations in an HIV infected population from south India and evaluate their association with HIV viral load and CD4/CD8 ratio. Intraoral examination of 103 patients, whose CD4/CD8 ratio was available, were conducted. HIV viral loads were available for thirty patients only. The prevalence of oral manifestations was 80.6% (83/103. The most common oromucosal lesion was erythematous candidiasis (EC (38.8% followed by melanotic hyperpigmentation (35.9%. Patients having any oral manifestation had a mean CD4/CD8 ratio of 0.24. EC had positive predictive value of 85.0% for CD4/CD8 ratio 20,000 copies/mL (20,000 copies/mL.

  13. 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 ...

  14. A higher frequency of circulating IL-22(+CD4(+ T cells in Chinese patients with newly diagnosed Hashimoto's thyroiditis.

    Directory of Open Access Journals (Sweden)

    Hui Guo

    Full Text Available BACKGROUND: IL-22 and IL-17A are implicated in the pathogenesis of autoimmune diseases. However, the role of IL-22(+ and IL-17A(+ CD4(+ T cells in the pathogenesis of Hashimoto's thyroiditis (HT is not fully understood. This study investigates serum IL-22 and IL-17A levels and determines the frequency of circulating IL-22(+ CD4(+ T cells in HT patients to understand their roles in the pathogenesis of HT. METHODS: The levels of serum IL-22, IL-17A and IFN-γ and the frequency of circulating IL-22(+CD4(+ and IL-17A(+CD4(+ T cells in 17 HT patients and 17 healthy controls (HC were determined by enzyme-linked immunosorbent assay (ELISA and flow cytometry. The levels of serum free triiodothyronine (FT4, free thyroxine (FT3, thyroid stimulating hormone (TSH, anti-thyroid peroxidase (TPO and anti-thyroglobulin antibodies (TgAb by chemiluminescent enzyme immunoassay and radioimmunoassay. RESULTS: The percentages of circulating IL-22(+CD4(+ and IL-17(+CD4(+ T cells (p<0.0001, p<0.0001 and the levels of serum IL-22, IL-17A and IFN-γ (p<0.0001, p<0.0001, p = 0.0210 in the HT patients were significantly higher than that in the HC. The percentages of IL-22(+CD4(+ T cells were positively correlated with Th17 cells (r = 0.8815, p<0.0001 and IL-17A(+IL-22(+CD4(+ T cells (r = 0.8914, p<0.0001, but were negatively correlated with Th1 cells (r = -0.6110, p<0.0092 in the HT patients. The percentages of Th22 cells, Th17 cells and IL-17A(+IL-22(+CD4(+ T cells were negatively correlated with the levels of serum TSH in the HT patients (r = -0.8402, p<0.0001; r = -0.8589, p<0.0001; r = -0.8289 p<0.0001, respectively. CONCLUSIONS: A higher frequency of circulating IL-22(+CD4(+ and IL-17A(+CD4(+ T cells may be associated with the development of HT in Chinese patients.

  15. 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

  16. [Cervical radiculopathy].

    Science.gov (United States)

    Kuijper, B

    2014-10-01

    Cervical radiculopathy is a common cause of pain in the arm. It is caused by nerve root compression in the neck, as a consequence of a herniated disc, or spondyliotic foraminal stenosis. It causes severe pain, especially during the first few weeks, and paraesthesias in the forearm and hand. Patients also suffer from neck pain and loss of strength in the relevant arm. The arm pain can be exacerbated by certain movements of the head; these should be avoided as much as possible. Diagnosis can be made on the basis of history and physical examination. The pain generally disappears without active patient treatment. A semi-rigid cervical collar is recommended to accelerate pain relief. In cases of persistent pain, surgery will be considered. In such cases an MRI should be performed to show the cause and level of nerve root compression. PMID:26185991

  17. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

    Directory of Open Access Journals (Sweden)

    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.

  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

    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

  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. 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

  1. Allergic Sensitization Underlies Hyperreactive Antigen-Specific CD4+ T Cell Responses in Coincident Filarial Infection.

    Science.gov (United States)

    Gazzinelli-Guimarães, Pedro H; Bonne-Année, Sandra; Fujiwara, Ricardo T; Santiago, Helton C; Nutman, Thomas B

    2016-10-01

    Among the various hypotheses put forward to explain the modulatory influence of helminth infection on allergic effector responses in humans, the IL-10-induced suppression of Th2-associated responses has been the leading candidate. To explore this helminth/allergy interaction more fully, parasite- and allergen-specific CD4(+) T cell responses in 12 subjects with filarial infections, and coincident allergic sensitization (filarial [Fil](+)allergy [A](+)) were compared with the responses to three appropriate control groups (Fil(-)A(-) [n = 13], Fil(-)A(+) [n = 12], Fil(+)A(-) [n = 11]). The most important findings revealed that Fil(+)A(+) had marked (p eosinophils (p eosinophil-derived neurotoxin [p < 0.01, r = 0.7059]). CD4(+) responses to allergen were not different (to a large extent) among the groups. Taken together, our data suggest that allergic sensitization coincident with filarial infection drives parasite Ag-specific T cell hyperresponsiveness, which is characterized largely by an augmented Th2-dominated immune response. PMID:27566825

  2. The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes.

    Science.gov (United States)

    Zhang, Qian; Wei, Fang; Wang, Hong Yi; Liu, Xiaobin; Roy, Darshan; Xiong, Qun-Bin; Jiang, Shuguang; Medvec, Andrew; Danet-Desnoyers, Gwenn; Watt, Christopher; Tomczak, Ewa; Kalos, Michael; Riley, James L; Wasik, Mariusz A

    2013-12-01

    With this study we have demonstrated that in vitro transduction of normal human CD4(+) T lymphocytes with NPM-ALK results in their malignant transformation. The transformed cells become immortalized and display morphology and immunophenotype characteristic of patient-derived anaplastic large-cell lymphomas. These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of immunosuppressive cytokine IL-10 and cell-surface protein PD-L1/CD274. Implantation of NPM-ALK-transformed CD4(+) T lymphocytes into immunodeficient mice resulted in formation of tumors indistinguishable from patients' anaplastic large-cell lymphomas. Our findings demonstrate that the key aspects of human carcinogenesis closely recapitulating the features of the native tumors can be faithfully reproduced in vitro when an appropriate oncogene is used to transform its natural target cells; this in turn points to the fundamental role in malignant cell transformation of potent oncogenes expressed in the relevant target cells. Such transformed cells should permit study of the early stages of carcinogenesis, and in particular the initial oncogene-host cell interactions. This experimental design could also be useful for studies of the effects of early therapeutic intervention and likely also the mechanisms of malignant progression.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Naturally Occurring Self-Reactive CD4+CD25+ Regulatory T Cells: Universal Immune Code

    Institute of Scientific and Technical Information of China (English)

    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".

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

    Directory of Open Access Journals (Sweden)

    Marco Antonio Moro-García

    2013-05-01

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

  6. Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes.

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    David R Collins

    2015-07-01

    Full Text Available Vpr is a conserved primate lentiviral protein that promotes infection of T lymphocytes in vivo by an unknown mechanism. Here we demonstrate that Vpr and its cellular co-factor, DCAF1, are necessary for efficient cell-to-cell spread of HIV-1 from macrophages to CD4+ T lymphocytes when there is inadequate cell-free virus to support direct T lymphocyte infection. Remarkably, Vpr functioned to counteract a macrophage-specific intrinsic antiviral pathway that targeted Env-containing virions to LAMP1+ lysosomal compartments. This restriction of Env also impaired virological synapses formed through interactions between HIV-1 Env on infected macrophages and CD4 on T lymphocytes. Treatment of infected macrophages with exogenous interferon-alpha induced virion degradation and blocked synapse formation, overcoming the effects of Vpr. These results provide a mechanism that helps explain the in vivo requirement for Vpr and suggests that a macrophage-dependent stage of HIV-1 infection drives the evolutionary conservation of Vpr.

  7. 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)

  8. Functional heterogeneity in CD4+ T cell responses against a bacterial pathogen

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    Ashley eViehmann Milam

    2015-12-01

    Full Text Available To investigate how CD4+ T cells function against a bacterial pathogen, we generated a Listeria monocytogenes-specific CD4+ T cell model. In this system, two TCRtg mouse lines, LLO56 and LLO118 recognize the same immunodominant epitope (LLO190-205 of Listeria monocytogenes and have identical in vitro responses. However, in vivo LLO56 and LLO118 display vastly different responses during both primary and secondary infection. LLO118 dominates in the primary response and in providing CD8 T cell help. LLO56 predominates in the secondary response. We have also shown that both specific (TCR-mediated and nonspecific stimuli (bypassing the TCR elicit distinct responses from the two transgenics, leading us to conclude that the strength of self-pMHC signaling during development tightly dictates the cell’s future response in the periphery. Herein, we review our findings in this transfer system, focusing on the contribution of the immunomodulatory molecule CD5 and the importance of self-interaction in peripheral maintenance of the cell. We also discuss the manner in which individual TCR affinities to foreign and self-pMHC contribute to the outcome of an immune response; our assertion is that there exists a spectrum of possible T cell responses to recognition of cognate antigen during infection, adding immense diversity to the immune system’s response to pathogens.

  9. Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study.

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    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.

  10. 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.

  11. Requirements for CD4+ cells and gamma interferon in resolution of established Cryptosporidium parvum infection in mice.

    OpenAIRE

    W. Chen; Harp, J A; Harmsen, A G

    1993-01-01

    The importance of CD4+ cells and gamma interferon (IFN-gamma) in the resolution of established Cryptosporidium parvum infection was investigated with a murine model of cryptosporidiosis in severe combined immunodeficient (SCID) mice. C. parvum-infected SCID mice were reconstituted with spleen cells from immunocompetent donors. The recipients were able to resolve their C. parvum infection by 17 days postreconstitution. Treatment of reconstituted SCID mice with either anti-CD4 monoclonal antibo...

  12. 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

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. Survey of Clinical Syndromes leading to Hospitalization in HIV Infected Patients According to CD4 count in Sina Hospital (Kermanshah

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    B. Sayad

    2006-10-01

    Full Text Available Introduction & Objective: Immunodeficiency duo to HIV infection can produce unusual diseases in infected individuals and CD4 count is the main predictor of the disease progression. In this study the clinical syndromes resulting hospitalization were considered according to CD4 count for the better diagnosis and treatment of clinical complications in HIV infected patients.Materials & Methods: This cross-sectional study was performed from March 2002 to March 2003 in Kermanshah Sina Hospital. HIV infection was confirmed with positive double ELISA and Western Blot. CD4 count was measured by flucytometery, clinical syndromes were collected with final diagnosis, and the rest of the data were gathered according to the patients' interviews. Statistical analysis was performed by SPSS 11.5. Results: During this study, 72 out of 215 admitted patients were enrolled. All of them were male with the mean age(SD of 33.49.1 years. 64 cases (88.9% were addicted and 40 cases (55.6% had prison history. Clinical and/or laboratory indicators of AIDS were observed in 32 cases (44.4%. The average of CD4 count was 356/L. Patients with lymphadenopathy, neurologic and pneumonia syndromes had the least count of CD4 with the averages of 90, 241 and 269/ L and patients with sepsis, endocarditis and hepatitis syndromes had the highest CD4 average count of 646, 394 and 373/L respectively. Statistical correlations were observed between pneumonia syndrome and CD4 300/ L, that shows the effect of CD4 count in appearance of clinical syndromes. Unsafe injections in prisoners may cause acquisition of viral hepatitis in these patients.

  18. GM-CSF production allows the identification of immunoprevalent antigens recognized by human CD4+ T cells following smallpox vaccination.

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    Valeria Judkowski

    Full Text Available The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a "T cell-driven" methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens.

  19. 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

  20. Selective Loss of Early Differentiated, Highly Functional PD1high CD4 T Cells with HIV Progression.

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    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.

  1. CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection

    Science.gov (United States)

    Buggert, Marcus; Frederiksen, Juliet; Lund, Ole; Betts, Michael R.; Biague, Antonio; Nielsen, Morten; Tauriainen, Johanna; Norrgren, Hans; Medstrand, Patrik; Karlsson, Annika C.; Jansson, Marianne

    2016-01-01

    Objective: HIV type 2 (HIV-2) represents an attenuated form of HIV, in which many infected individuals remain ‘aviremic’ without antiretroviral therapy. However, aviremic HIV-2 disease progression exists, and in the current study, we therefore aimed to examine if specific pathological characteristics of CD4+ T cells are linked to such outcome. Design: HIV-seronegative (n = 25), HIV type 1 (HIV-1) (n = 33), HIV-2 (n = 39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n = 13)-infected study participants were enrolled from an occupational cohort in Guinea-Bissau. Methods: CD4+ T-cell differentiation, activation, exhaustion, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4+ T-cell subpopulations linked to infection type and disease stage. Results: HIV-2-infected individuals had early and late-differentiated CD4+ T-cell clusters with lower activation (CD38+HLA-DR+) and exhaustion programmed death-1 (PD-1) than HIV-1 and HIV-D-infected individuals. We also noted that aviremic HIV-2-infected individuals possessed fewer individuals. CD4+ T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegative individuals, aviremic HIV-2-infected individuals had T-bet+ CD4+ T cells that showed elevated immune activation/exhaustion, and particularly the frequencies of PD-1+ cells were associated with a suboptimal percentage of CD4+ T cells. Conclusion: Increased frequencies of CD4+ T cells with an activated/exhausted phenotype correlate with exacerbated immunodeficiency in aviremic HIV-2-infected individuals. Thus, these findings encourage studies on the introduction of antiretroviral therapy also to individuals with aviremic HIV-2 infection. PMID:27525551

  2. Screening of aplastic anaemia-related genes in bone marrow CD4+ T cells by suppressive subtractive hybridization

    Institute of Scientific and Technical Information of China (English)

    ZHENG Miao; LIU Wen-li; FU Jin-rong; SUN Han-ying; ZHOU Jian-feng; XU Hui-zhen

    2007-01-01

    Background CD4+ T cells play a crucial role in the pathogenesis of aplastic anaemia. However, the mechanisms of over-proliferation, activation, infiltration of bone marrow and damage to haematopoietic cells of CD4+ T cells in aplastic anaemia are unclear. Therefore, we screened differentially expressed genes of bone marrow CD4+ T cells of aplastic anaemia patients and normal donors by suppressive subtractive hybridization to investigate the pathogenesis of aplastic anaemia.Methods The bone marrow mononuclear cells of a first visit aplastic anaemia patient and a healthy donor of the same age and sex were isolated using lymphocyte separating medium by density gradient centrifugation. With the patients as "tester" and donor as "driver", their CD4+T cells were separated with magnetic bead sorting and a cDNA library established by suppressive subtractive hybridization. Then 15 of the resulting subtracted cDNA clones were randomly selected for DNA sequencing and homological analysis. With semiquantitative RT-PCR, bone marrow samples from 20 patients with aplastic anaemia and 20 healthy donors assessed the expression levels of differentially expressed genes from SSH library.Results PCR detected 89 clones in the library containing an inserted fragment of 100 bp to 700 bp. Among 15 sequenced clones, 12 were known genes including 3 repeated genes. Compared with normal donors, there were 9/12 genes over-expressed in bone marrow CD4+T cells of patients with aplastic anaemia. The effects of these genes included protein synthesis, biology oxidation, signal transduction, proliferative regulation and cell migration. Not all these genes had been reported in the mechanisms of haematopoietic damage mediated by CD4+ T cells in aplastic anaemia.Conclusions Screening and cloning genes, which regulate functions of CD4+ T cells, are helpful in elucidating the mechanisms of over proliferation, activation, infiltrating bone marrow and damaging haematopoietic cells of CD4+ T cells in

  3. 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....

  4. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >=300 cells/μL and HIV-1 suppression?

    Science.gov (United States)

    Gale, Howard B; Gitterman, Steven R; Hoffman, Heather J; Gordin, Fred M; Benator, Debra A; Labriola, Ann M; Kan, Virginia L

    2013-05-01

    Among patients infected with human immunodeficiency virus (HIV), those with HIV-1 RNA HIV causes of CD4 lymphopenia were excluded, the probability rose to 99.2%. Our data support less frequent CD4 monitoring during viral suppression.

  5. 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

  6. 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 with non......-activated CD4+ T cells. In pulse-chase experiments it was shown that BrdU-labeled cells disappeared rapidly from the lamina propria of diseased mice. DNA analysis revealed that this was due to the presence of nearly four times as many apoptotic CD4+ T cells in diseased than in control mice. Further analyses...

  7. TLR2 engagement on CD4(+) T cells enhances effector functions and protective responses to Mycobacterium tuberculosis.

    Science.gov (United States)

    Reba, Scott M; Li, Qing; Onwuzulike, Sophia; Ding, Xuedong; Karim, Ahmad F; Hernandez, Yeritza; Fulton, Scott A; Harding, Clifford V; Lancioni, Christina L; Nagy, Nancy; Rodriguez, Myriam E; Wearsch, Pamela A; Rojas, Roxana E

    2014-05-01

    We have previously demonstrated that mycobacterial lipoproteins engage TLR2 on human CD4(+) T cells and upregulate TCR-triggered IFN-γ secretion and cell proliferation in vitro. Here we examined the role of CD4(+) T-cell-expressed TLR2 in Mycobacterium tuberculosis (MTB) Ag-specific T-cell priming and in protection against MTB infection in vivo. Like their human counterparts, mouse CD4(+) T cells express TLR2 and respond to TLR2 costimulation in vitro. This Th1-like response was observed in the context of both polyclonal and Ag-specific TCR stimulation. To evaluate the role of T-cell TLR2 in priming of CD4(+) T cells in vivo, naive MTB Ag85B-specific TCR transgenic CD4(+) T cells (P25 TCR-Tg) were adoptively transferred into Tlr2(-/-) recipient C57BL/6 mice that were then immunized with Ag85B and with or without TLR2 ligand Pam3 Cys-SKKKK. TLR2 engagement during priming resulted in increased numbers of IFN-γ-secreting P25 TCR-Tg T cells 1 week after immunization. P25 TCR-Tg T cells stimulated in vitro via TCR and TLR2 conferred more protection than T cells stimulated via TCR alone when adoptively transferred before MTB infection. Our findings indicate that TLR2 engagement on CD4(+) T cells increases MTB Ag-specific responses and may contribute to protection against MTB infection.

  8. 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)

  9. The role of CD4 T cell memory in generating protective immunity to novel and potentially pandemic strains of influenza

    Directory of Open Access Journals (Sweden)

    Anthony eDiPiazza

    2016-01-01

    Full Text Available Recent events have made it clear that potentially pandemic strains of influenza regularly pose a threat to human populations. Therefore, it is essential that we develop better strategies to enhance vaccine design and evaluation, to predict those that will be poor responders to vaccination and to identify those that are at particular risk of disease-associated complications following infection. Simplified animal models have revealed the discrete functions that CD4 T cells play in the developing immune response and to influenza immunity. However, humans have a complex immunological history with influenza through periodic infection and vaccination with seasonal variants, leading to the establishment of heterogeneous memory populations of CD4 T cells that participate in subsequent responses. The continual evolution of the influenza-specific CD4 T cell repertoire involves both specificity and function and overlays other restrictions on CD4 T cell activity derived from viral antigen handling and MHC class II:peptide epitope display. Together, these complexities in the influenza-specific CD4 T cell repertoire constitute a formidable obstacle to predicting protective immune response to potentially pandemic strains of influenza and in devising optimal vaccine strategies to potentiate these responses. We suggest that more precise efforts to identify and enumerate both the positive and negative contributors within the CD4 T cell compartment will aid significantly in achievement of these goals.

  10. 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

  11. 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.

  12. Oral vaccination with lipid-formulated BCG induces a long-lived, multifunctional CD4(+ T cell memory immune response.

    Directory of Open Access Journals (Sweden)

    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.

  13. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients

    Science.gov (United States)

    Kovacs, Joseph A.; Lempicki, Richard A.; Sidorov, Igor A.; Adelsberger, Joseph W.; Sereti, Irini; Sachau, William; Kelly, Grace; Metcalf, Julia A.; Davey, Richard T.; Falloon, Judith; Polis, Michael A.; Tavel, Jorge; Stevens, Randy; Lambert, Laurie; Hosack, Douglas A.; Bosche, Marjorie; Issaq, Haleem J.; Fox, Stephen D.; Leitman, Susan; Baseler, Michael W.; Masur, Henry; Di Mascio, Michele; Dimitrov, Dimiter S.; Lane, H. Clifford

    2005-01-01

    HIV infection leads to decreases in the number of CD4+ T lymphocytes and an increased risk for opportunistic infections and neoplasms. The administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound increases (often greater than 100%) in CD4 cell number and percentage. Using in vivo labeling with 2H-glucose and BrdU, we have been able to demonstrate that, although therapy with IL-2 leads to high levels of proliferation of CD4 as well as CD8 lymphocytes, it is a remarkable preferential increase in survival of CD4 cells (with half-lives that can exceed 3 years) that is critical to the sustained expansion of these cells. This increased survival was time-dependent: the median half-life, as determined by semiempirical modeling, of labeled CD4 cells in 6 patients increased from 1.7 weeks following an early IL-2 cycle to 28.7 weeks following a later cycle, while CD8 cells showed no change in the median half-life. Examination of lymphocyte subsets demonstrated that phenotypically naive (CD27+CD45RO–) as well as central memory (CD27+CD45RO+) CD4 cells were preferentially expanded, suggesting that IL-2 can help maintain cells important for host defense against new antigens as well as for long-term memory to opportunistic pathogens. PMID:16025158

  14. [Parameters of the CD4-Cell count and viral load in human immunodeficiency virus type 1 (HIV-1) infected patients].

    Science.gov (United States)

    Selimova, L M; Serebrovskaya, L V; Ivanova, L A; Kravchenko, A V; Buravtsova, E V

    2015-01-01

    In this work the specific features of parameters of plasma CD4 T-lymphocytes count and level virus RNA in the HIV-infected patients were studied. 22% correlation between reduction of CD4 cell count and an increase in virus RNA level was observed in persons that did not receive antiretroviral treatment during the third HIV-infection phase. During this phase of infection patients exhibited a growth of the median value of virus load in cases of both rise as decline in CD4 cell count during long observation period. In addition, towards the end of the observation period, the percentage of patients with virus load > 3.3 Ig copies/ml considerably expanded. 43% correlation between CD4 cell count and duration of the HIV-infection was detected during the fourth infection phase in persons that did not receive antiretroviral treatment. Most of the patients in the third and the fourth infection phases had essential CD4 cell count growth during antiretroviral treatment. Best values were observed in patients with the initial value of CD4 > 400 cells/μl belonging to the third HIV-infection phase.

  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. 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)

  17. 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.

  18. 内蒙古新发现HIV感染者首次CD4+T淋巴细胞检测分析%Analysis of CD4+ T lymphocytes for new found HIV-infected person in Inner Mongolia

    Institute of Scientific and Technical Information of China (English)

    杨虹; 武玉梅; 迟富利; 杨景元

    2012-01-01

    Objective:To understand the immune status and disease progression of HIV infection in Inner Mongo-lia through detection and analysis of CD4 + T lymphocytes for the first time. Methods: Flow cytometry was used on whole blood samples for the detection of CD4 + T lymphocytes absolute value, and the measured values were analyzed by statistics. Results: The CD4 + T lymphocytes mean of 182 cases with HIV infection were 459. 85 ±240. 21/μl. The difference of CD4 + T lymphocytes absolute value had statistical difference among HIV - infected patients in dif-ferent age groups ( F = 9. 509 , P = 0. 0001 * * < 0. 05 ) , and with age increasing, the CD4 + T lymphocytes absolute value hold a downward trend. Conclusion: One third of the new - found HIV - infected cases has entered the period of AIDS, need to monitor the disease progress and accept antiviral therapy. Propaganda of HIV - related knowledge, early diagnosis, early intervention and early management should be strengthened to improve the survival quality of HIV - infected patients.%目的:通过对内蒙古地区新发现的HIV感染者首次CD4+T淋巴细胞进行检测分析,了解其免疫状况及疾病进展情况.方法:采用流式细胞术对采集的全血样本进行CD4+T淋巴细胞绝对值检测,统计分析其测定值.结果:能随访到的182例HIV感染者CD4+T淋巴细胞绝对值的均值为(459.85 ±240.21)个/μl.不同年龄组HIV感染者间CD4+T淋巴细胞绝对值差异具有统计学意义(F=9.509,P=0.0001** <0.05),且随年龄增长CD4+T淋巴细胞绝对值具有下降趋势.结论:内蒙古新发现HIV感染者中1/3已进入艾滋病期,需要监测疾病进程并及时对其进行抗病毒治疗.加强宣传,早发现、早干预、早管理,以提高HIV感染者的生存质量.

  19. 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

  20. The CD4+CD26-T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile

    NARCIS (Netherlands)

    Ma, Yue; Visser, Lydia; Blokzijl, Tjasso; Harms, Geert; Atayar, Cigdem; Poppema, Sibrand; van den Berg, Anke

    2008-01-01

    Little is known about the gene expression profile and significance of the rosetting CD4+CD26- T cells in classical Hodgkin's lymphoma (cHL). To characterize these T cells, CD4+CD26- and CD4+CD26+ T-cell populations were sorted from lymph node (LN) cell suspensions from nodular sclerosis HL (NSHL) an

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