Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection
Alexis YeroTao ShiOmar FarnósJean‐Pierre RoutyCécile TremblayMadéleine DurandChristos TsoukasCecilia T. CostiniukMohammad‐Ali Jenabian
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HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied.Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology.Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different.Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression.This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).Keywords:
Regulatory T cell
Objective To investigate the changes of CD4+ CD25+ Foxp3+ regulatory T cell and IL-10,TGF-β1 in steroid-resistant asthma patients of peripheral blood,to study their significance.Methods The CD4+ CD25+ Foxp3+ regulatory T cell in 40 cases steroid-resistant asthma patients were detected by flow cytometry.The levels of serum IL-10 and TGF-β1 were detected by ELISA.The control groups were 30 individuals having general physical examination and 46 patients with steroid-sensitive patients.Results The proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell and the levels of serum IL-10,TGF-β1 in steroid-resistant asthma group of Peripheral Blood were decreased significantly than steroid-sensitive group and healthy control group (P ＜0.01,P ＜0.05).The proportion and number of CD4+CD25+ Foxp3+ regulatory T cell and the levelsof serum TGF--β1 in steroid-sensitive group were decreased significantly than healthy control group,but the levels of serum IL-10 were no statistical difference between them.The proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell were positively correlated with the serum IL-10,TGF-β1 (P ＜0.01).Conclusions Lower proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell and lower IL-10,TGF-β1 were observed in steroid-resistant asthma patients,which might play an important role in occurrence and development of steroid-resistant asthma.
Key words:
Steroid-resistant asthma; Regulatory T cell; Transforming growth factor-β1; Interleukin-10
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Abstract Despite intense research on the role of the regulatory T cells (Treg) , the kinetics of regulatory T cells in the early development of T1D is still not clear. We have examined the proportions of CD4+CD25+Foxp3+ regulatory T (Treg) cells and CD4+ T helper (Th) cells at close intervals in the multiple low dose streptozotocin (MLDSTZ) murine diabetes model using flow cytometry, PCR and immunostaining. The Foxp3 mRNA levels were elevated in the spleen, pancreas and PDLNs of MLDSTZ treated mice. Foxp3 immunostaining in pancreas and spleen suggested that the infiltration of Treg cells increased in pancreas and spleen of MLDSTZ treated mice. The proportions of CD4+CD25+FoxP3+ Treg cells increased in MLDSTZ treated mice from day 7 in pancreatic draining lymph nodes (PDLNs) and day 21 in spleen. The proportions of CD4+ Th cells in MLDSTZ treated mice decreased on day 7 but increase from day 10, at which time the numbers of Tregs increased suggesting that the increase in Tregs fail to control the ongoing immune insult. Impaired mRNA expression levels of IL-35 and IL-10 in PDLNs and spleen of MLDSTZ suggest a functional impairment of the Tregs. Elevated IL-17 mRNA level in spleen of MLDSTZ mice on day 21 further provide evidence of a functional defect in the Tregs. In conclusion Tregs are upregulated in the development of MLDSTZ. However, the upregulation does not protect from hyperglycemia possibly because of a functional deficiency in the Treg population in MLDSTZ treated mice.
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Physiological changes during normal pregnancy are characterized by an inflammatory immune response and insulin resistance. Therefore, we hypothesize that gestational diabetes mellitus (GDM) may be caused by an inappropriate adaption of the maternal immune system to pregnancy. In this study we examined the role of regulatory T cell (Treg) differentiation for the development of GDM during pregnancy. We used six-colour flow cytometric analysis to demonstrate that the total CD4(+) CD127(low+/-) CD25(+) forkhead box protein 3 (FoxP3(+)) T(reg) pool consists of four different T(reg) subsets: naive CD45RA(+) T(regs), HLA-DR(-) CD45RA(-) memory T(regs) (DR(-) T(regs)) and the highly differentiated and activated HLA-DR(low+) CD45RA(-) and HLA-DR(high+) CD45RA(-) memory T(regs) (DR(low+) and DR(high+) T(regs)). Compared to healthy pregnancies, the percentage of CD4(+) CD127(low+/-) CD25(+) FoxP3(+) T(regs) within the total CD4(+) T helper cell pool was not different in patients affected by GDM. However, the suppressive activity of the total CD4(+) CD127(low+/-) CD25(+) T(reg) pool was significantly reduced in GDM patients. The composition of the total T(reg) pool changed in the way that its percentage of naive CD45RA(+) T(regs) was decreased significantly in both patients with dietary-adjusted GDM and patients with insulin-dependent GDM. In contrast, the percentage of DR(-) -memory T(regs) was increased significantly in patients with dietary-adjusted GDM, while the percentage of DR(low+) and DR(high+) memory T(regs) was increased significantly in patients with insulin-dependent GDM. Hence, our findings propose that alterations in homeostatic parameters related to the development and function of naive and memory T(regs) may cause the reduction of the suppressive capacity of the total T(reg) pool in GDM patients. However, as this is an exploratory analysis, the results are only suggestive and require further validation.
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In the pathogenesis of MS, impairment of peripheric immune tolerance plays an important critical role in the emergence of autoimmunity. The regulatory T cells play a crucial role in the healthy function of immune tolerance. FoxP3 is a transcription factor which assignment for enough regulatory T cell expression. We compared the total percentage CD4(+) and FoxP3 expression in T lymphocytes in 31 cases including 12 RRMS, 11 SRMS and eight attack which has a definite MS regarding Mc Donald's criteria 12 healthy subjects for regulatory T cell subtypes with analysis flow cytometry in haematology laboratory. Also, we compared 7 cases in a group of 8 RRMS with an attack for before and after 1000 mg/day IVMP. The results have assesment as statistical. The regulatory cell profiles CD4(+) CD25(+), CD4(+) foxP3(+), CD4(+) CD25(+) foxP3(+),CD4(+) CD25(+) foxP3(-), and CD4(+) CD25(-) foxP3(+)of all patients were compared with the healthy control group.No significant differences existed between the groups (p>0.005). The results of regulatory cell profiles and foxP3 expression of 7 patients with attacks before treatment and after IVMP treatment were not significant (p>0.05). However, high-dose intravenous methylprednisolone therapy (IVMP) treatment was observed to cause a slight numerical increase in regulatory cell subtypes. As a consequence, we thought that the regulatory T cells play an important role in the immunopathogenesis of MS as well as its numerical sufficiency.
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Introduction: Inflammation and joint stiffening are common symptoms of rheumatoid arthritis (RA), an autoimmune inflammatory disease. Previous treatments of RA have focused on decreasing symptomatic effects but have limited effects on disease progression. In RA, an influx of pro-inflammatory cytokines occurs at the synovium, which is the soft tissue surrounding the joints. The production of pro-inflammatory cytokines is controlled by regulatory T-cells, which have a deficit in function in RA patients. Regulatory T-cell development and function is regulated by the forkhead box P3 (FOXP3). The FOXP3 gene is a viable therapeutic target to restore regulatory T-cell functionality because FOXP3 is underexpressed in RA patients. Therefore, this study ventures to treat RA regulatory T-cell functionality by increasing FOXP3 gene expression through FOXP3 recombinant Lactobacillus plantarum bactofection. We hypothesize that bactofection will lead to a decrease in RA progression by restoring normal function in regulatory T-cells, thus decreasing inflammation. Methods: We propose a study using severe combined immunodeficient mouse models engrafted with human RA synovium. The mice will be given either no treatment (control group) or a 2×109 CFU/g dose of recombinant Lactobacillus plantarum strain. The mice will be sacrificed after 0 days, 10 days, 20 days, and 30 days (control group and treatment groups respectively). Synovial tissue samples will be obtained from the hip joints. Through immunofluorescence and western blotting, the prevalence of FOXP3, regulatory T-cells and pro-inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-1 and Interleukin-6 will be compared between the control and treatment groups. For statistical analysis, a one-way MANOVA test, Levene’s test, and a Shapiro-Wilk test will be performed using GraphPad Prism. Results: As a result of bactofection, there will be an increase in FOXP3 and regulatory T-cells, resulting in a decrease of pro-inflammatory cytokines. Discussion: Analysis of mice treated with recombinant Lactobacillus plantarum compared to mice with no treatment will set a correlation between FOXP3, regulatory T-cells, and pro-inflammatory cytokines prevalence and RA progression after treatment. Conclusion: The findings of this study will provide evidence that bactofection is a viable treatment for RA, and may be more effective than conventional treatments.
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