Frequency Of IFNγ-producing CD4 Research Articles

Functional exhaustion of CD4<sup>+</sup>T cells in HIV/HCV coinfected HAART-treated patients

Infection with hepatitis C virus (HCV) is common among HIV-positive patients, with up to 50% of them being coinfected in Russia. While highly active antiretroviral therapy (HAART) suppresses HIV replication and restores the immune system of HIV-infected subjects, HCV coinfection interferes with CD4+T cell regeneration and increases the risk of patients’ morbidity and mortality. During HAART, HIVinfection progression and the immune system restoration efficiency largely depend on immune activation and CD4+T cell exhaustion. This study determined the level of activation, exhaustion, and cytokine production in CD4+T cells obtained from the peripheral blood of HAART-treated HIV/HCV coinfected and HIV monoinfected subjects. The study comprised 11 HIV/HCV coinfected individuals and 10 HIV monoinfected patients receiving HAART for more than two years, with a control group of 10 volunteers without the signs of HIV or HCV infections. Compared with healthy controls, HIV/HCV coinfected patients had an increased frequency of activated CD38+HLA-DR+ CD4+T lymphocytes (p < 0.05), a higher level of CD4+T cell exhaustion determined according to the TIGIT expression density per cell (p < 0.05), and a greater proportion of interferon-gamma (IFNγ)-producing CD4+T lymphocytes following activation (p < 0.05). The frequency of IFNγ-producing CD4+T cells in the donors’ blood positively correlated with the proportion of activated CD4+T cells (R = 0.514, p < 0.01). Despite having a large number of IFNγ-producing CD4+T lymphocytes, the HIV/HCV coinfected patients’ average production of IFNγ by CD4+T cells was significantly lower than that in healthy controls (p < 0.05). The IFNγ production in CD4+T lymphocytes did not depend on activation (p > 0.05). However, a negative correlation was established between the IFNγ production and the level of CD4+T cell exhaustion (R = -0.400, p < 0.05). The letter was also found to inversely correlate with the CD4+T cell counts in the donors’ peripheral blood (R = -0.598, p < 0.01). These data suggest that HCV coinfection leads to pronounced functional exhaustion of CD4+T cells and may aggravate the course of HIVinfection in patients receiving HAART.

Peptide microarray-based identification of dormancy-associated Mycobacterium tuberculosis antigens inducing immune responses among latent tuberculosis infection individuals in Thailand

Multi-stage tuberculosis (TB) vaccines composed of active- and dormancy-associated antigens are promising to trigger the immune protection against all TB stages. However, scientists are still in quest of the suitable vaccine candidates. In this study, we identified the potential targets for this vaccine in a high TB burden country, Thailand. Peptide microarray was applied to gauge IgA and IgG antibodies specific to 16,730 linear epitopes of 52 dormancy-associated Mycobacterium tuberculosis (M. tb) proteins in three study groups: active tuberculosis (ATB), latent tuberculosis infection (LTBI) and endemic healthy control (EHC). Preferential IgA recognition against epitopes of dormancy-associated proteins was identified in LTBI group. Validation of these findings revealed that LTBI subjects exhibited the greater levels of Rv2659c- and Rv1738-specific IgA than those of household contacts, but less than did ATB subjects. Frequencies of IFNγ-producing CD4+ and CD8+ T cells induced by proteins Rv2659c and Rv1738 were higher in LTBI than ATB individuals. The results indicated that LTBI group in a high TB burden country demonstrated cell-mediated immune response to proteins Rv2659c and Rv1738 stronger than those of ATB. These immune responses likely contribute to natural protection against dormant M. tb and might be potential targets for a multi-stage TB vaccine.

Reformulating Small Molecules for Cardiovascular Disease Immune Intervention: Low-Dose Combined Vitamin D/Dexamethasone Promotes IL-10 Production and Atheroprotection in Dyslipidemic Mice.

The targeting of proinflammatory pathways has a prophylactic and therapeutic potential on atherosclerotic cardiovascular diseases (CVD). An alternative/complementary strategy is the promotion of endogenous atheroprotective mechanisms that are impaired during atherosclerosis progression, such as the activity of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg). There is a need to develop novel low cost, safe and effective tolDC/Treg-inducing formulations that are atheroprotective and that can be of easy translation into clinical settings. We found that apolipoprotein E-deficient (ApoE–/–) mice treated with a low-dose combined formulation of Vitamin D and Dexamethasone (VitD/Dexa), delivered repetitively and subcutaneously (sc) promoted interleukin-10 (IL-10) production by dendritic cells and other antigen presenting cells in the lymph nodes draining the site of injection and the spleens. Expectedly, the treatment also increased the numbers of IL-10-producing CD4+ T cells. Concomitantly, the frequency of IFNγ-producing CD4+ and CD8+ T cells in the spleen, and the IFNγ response of splenocytes to polyclonal stimulation ex vivo were lower after VitD/Dexa treatment, indicating a reduced proatherogenic Th1 response. Interestingly, VitD/Dexa-treated mice had smaller atherosclerotic lesions, with reduced lipid content and lower inflammatory infiltrate of macrophages and T cells in the aortic root. No hypolipidemic or antioxidant effect could be detected, suggesting that a dominantly immunomodulatory mechanism of atheroprotection was engaged under the low-dose sc VitD/Dexa conditions used. Finally, no evidence of clinical, biochemical or immune toxicity was observed in treated ApoE–/– mice and, most importantly, C57BL/6 mice latently infected with Leishmania parasites and treated with an identical VitD/Dexa dose/scheme showed no clinical or microbiological signs of disease reactivation, suggesting the absence of general immunosuppression. Altogether, these results indicate that a non-toxic, non-immunosuppressive, low-dose of VitD/Dexa, administered subcutaneously and repetitively, exerts atheroprotective effects in dyslipidemic mice, apparently due to the induction of an IL-10-producing network of lymphoid and myeloid immune cells. These well known, widely available, and inexpensive small molecules can be easily co-formulated into a simple and accessible agent with a potential use as a prophylactic or therapeutic immune intervention for CVD and other chronic inflammatory diseases.

Innate-like T cells in children with sickle cell disease.

BackgroundThe implication of lymphocytes in sickle cell disease pathogenesis is supported by a number of recent reports. These studies provided evidence for the activation of invariant natural killer T (iNKT) cells in adult patients, but did not investigate the involvement of other innate-like T cell subsets so far.MethodsHere we present a monocentric prospective observational study evaluating the number and functional properties of both circulating conventional and innate-like T cells, namely iNKT, Mucosal-Associated Invariant T (MAIT) and gammadelta (γδ) T cells in a cohort of 39 children with sickle cell disease.ResultsRelative to age-matched healthy controls, we found that patients had a higher frequency of IL-13- and IL-17-producing CD4+ T cells, as well as higher MAIT cell counts with an increased frequency of IL-17-producing MAIT cells. Patients also presented increased Vδ2 γδ T cell counts, especially during vaso-occlusive crisis, and a lower frequency of IFNγ-producing Vδ2 γδ T cells, except during crisis. iNKT cell counts and the frequency of IFNγ-producing iNKT cells were unchanged compared to controls. Our study revealed positive correlations between 1) the frequency of IFNγ-producing CD4+, CD8+ and Vδ2 γδ T cells and the number of hospitalizations for vaso-occlusive crisis in the previous year; 2) the frequency of IFNγ-producing iNKT cells and patients’ age and 3) the frequency of IL-17-producing Vδ2 γδ T cells and hemoglobin S level.ConclusionThese results strongly suggest a role of innate-like T cells in sickle cell disease pathophysiology, especially that of IL-17-producing MAIT and γδ T cells.

Modeling the Effect of the Aryl Hydrocarbon Receptor on Transplant Immunity.

BackgroundExposure to pollutants through inhalation is a risk factor for lung diseases including cancer, asthma, and lung transplant rejection, but knowledge of the effects of inhaled pollutants on pathologies outside of the lung is limited.MethodsUsing the minor-mismatched model of male C57BL/6J (B6) to female B6 skin grafts, recipient mice were treated with an inhaled urban dust particle sample every 3 days before and after grafting. Graft survival time was determined, and analysis of the resulting immune response was performed at time before rejection.ResultsSignificant prolongation of male skin grafts occurred in recipient female mice treated with urban dust particles compared with controls and was found to be dependent on aryl hydrocarbon receptor (AHR) expression in the recipient mouse. T cell responses to the male histocompatibility antigen (H-Y) Dby were not altered by exposure to pollutants. A reduction in the frequency of IFNγ-producing CD4 T cells infiltrating the graft on day 7 posttransplant was observed. Flow cytometry analysis revealed that AHR expression is upregulated in IFNγ-producing CD4 T cells during immune responses in vitro and in vivo.ConclusionsSurprisingly, inhalation of a pollutant standard was found to prolong graft survival in a minor-mismatched skin graft model in an AHR-dependent manner. One possible mechanism may be an effect on IFNγ-producing CD4 T cells responding to donor antigen. The increased expression of AHR in this CD4 T cell subset suggests that AHR ligands within the particulate matter may be directly affecting the type 1 T helper cell response in this model.

Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

IntroductionTh17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4-positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity.MethodsFlow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13).ResultsThe frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17-producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFα) was significantly increased in SFMC (P = 0.0068). The frequency of IFNγ-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNγ. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression.ConclusionsThese findings demonstrate a modest enrichment of IL-17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFα than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients.

Kinetics of Th17 development in type 1 diabetes (135.35)

Abstract Type 1 diabetes (T1D) is an autoimmune disease. It has been established that Th1 cells play a central role in the autoimmune attack against islet β cells. The Th17 subset has recently been implicated in many autoimmune disease models. However, its role in T1D is still unclear. In diabetic NOD mice, we found elevated serum IL-17 levels and IL-17 producing infiltrating CD4+ T cells from islets. Adoptive transfer of in vitro differentiated islet-antigen-specific Th17 cells induced diabetes in recipient NOD.Scid mice with similar kinetics of that induced by Th1 cells. These data suggest a possible causal role of Th17 cell in T1D. To study the development of Th17 cells in vivo, we transferred naïve CD4+ T cells into neonatal NOD mice, and monitored phenotype and function of both transferred and endogenous T cells for up to 35 weeks. Surprisingly, we were able to identify islet infiltrating endogenous CD4+ T cells that expressed either IFNγ or IL-17 in 2-week-old NOD mice. Transferred naïve cells proliferated in recipients; they rapidly acquired effector memory phenotype and effector cytokine production. As expected, the frequency of IFNγ-producing CD4+ T cells increased over time in both endogenous and transferred populations. In contrast, the frequency of IL17-producing CD4+ T cells did not significantly change over time. These data suggest that, in T1D model, the Th17 cells may be a dynamic population with constant turnover rate, while contributing to diabetes pathogenesis.