Liver fibrosis and accelerated immune dysfunction (immunosenescence) among HIV-infected Russians with heavy alcohol consumption - an observational cross-sectional study

Abstract Background The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. Methods ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing CD28-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. Results Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. Conclusions Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.

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Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C

Scientific Reports ◽

10.1038/s41598-020-73137-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sylwia Osuch ◽

Tomasz Laskus ◽

Hanna Berak ◽

Karol Perlejewski ◽

Karin J. Metzner ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Chronic Hepatitis ◽

Hepatitis C ◽

T Cell ◽

Liver Fibrosis ◽

Programmed Cell Death ◽

Chronic Hepatitis C ◽

Programmed Cell Death 1 ◽

Advanced Liver Fibrosis

Abstract During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76 DAA-treated HCV-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4+PD-1+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cells and IL-10 levels measured by ELISA were significantly higher and CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells were significantly lower in patients than in controls. Treatment resulted in significant decrease of CD4+Tim-3+, CD8+Tim-3+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cell frequencies as well as IL-10 levels and increase in CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells. There were no significant changes in the frequencies of CD4+PD-1+ T-cells, while CD8+PD-1+ T-cells increased. Patients with advanced liver fibrosis had higher PD-1 and lower Tim-3 expression on CD4+T-cells and treatment had little or no effect on the exhaustion markers. HCV-specific CD8+T-cells frequency has declined significantly after treatment, but their PD-1 and Tim-3 expression did not change. Successful treatment of chronic hepatitis C with DAA is associated with reversal of immune exhaustion phenotype, but this effect is absent in patients with advanced liver fibrosis.

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Early Homeostatic Expansion of Regulatory T Cells with the Predominant Effector/Memory Phenotype May Stabilize Immune Recovery in the First Month after HSCT

Blood ◽

10.1182/blood.v124.21.2501.2501 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2501-2501

Author(s):

Takanori Yoshioka ◽

Yusuke Meguri ◽

Takeru Asano ◽

Taro Masunari ◽

Kumiko Kagawa ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Phase ◽

Cd4 T Cells ◽

Chronic Phase ◽

T Cell Subsets ◽

Effector Memory ◽

Ki 67 ◽

Memory Phenotype ◽

Post Transplant

Abstract CD4+Foxp3+ regulatory T cells (Treg) play a central role in establishing immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). We previously reported that the long-term severe lymphopenia could result in the collapse of Treg homeostasis leading to the onset of chronic GVHD (Matsuoka et al. JCI 2010). However, Treg homeostasis in the very early phase after HSCT has not been well studied. To address this issue, we here examined the early lymphocytes reconstitution in total 34 patients who received HSCT. Peripheral blood samples were obtained at 2, 4, 8 and 12 weeks after transplant and analyzed the reconstitution of CD4+CD25med-highCD127lowFoxp3+ Treg comparing with CD4+CD25neg-lowCD127highFoxp3- conventional T cell (Tcon) and CD8+ T cells. CD4 T cell subsets are further divided into subpopulations by the expression of CD45RA and CD31. The expressions of Helios, Ki-67, Bcl-2 and C-C chemokine receptor type 4 (CCR4) on these subsets were also examined. These patients were transplanted the grafts from various stem cell sources (7 HLA-matched PBSCT, 12 HLA-matched BMT, 6 HLA-mismatched CBT and 9 HLA-haploidentical PBSCT) and this enables us the opportunity to comparatively evaluate the early lymphocyte reconstitution among the different types of HSCT. After transplant, total lymphocyte counts were significantly lower than the counts before the start of conditioning (median lymphocytes 113/ul at 2 weeks and 223/ul at 4 weeks vs 550/ul before conditioning, P<0.01 and P<0.01, respectively). In the severely lymphopenic condition in the first month after HSCT, all T cell subsets were undergoing aggressive proliferation in this acute phase as compared to proliferation in the chronic phase, however, Treg proliferation was significantly higher than in Tcon at 4 weeks (%Ki-67+ cells; median 56.4%, 23.4%, respectively, P<0.02). %Treg of total CD4 T cells elevated and peaked at 4 weeks post-transplant. At this timepoint, %Treg of CD4 T cells showed the clear inverse correlation with %CD45RA+ of Treg (r2=0.40), suggesting the expansion of Treg in this phase appears to be a result from severe lymphopenia-driven proliferation which involves conversion from naive into memory phenotype. Elevation of %Treg was most evident in the patients who received HLA-haploidentical graft after ATG-containing conditioning (median 8.41% in haplo-HSCT, 5.25% in other groups, P<0.05), again indicating the lymphopenia is critical factor to drive Treg proliferatrion. Expanded Treg showed a predominant Helios+CD45RA-CD31- effector/memory phenotype with the lower level of Bcl-2 expression as compared to CD45RA+ naïve Treg. The elevation of Treg did not sustain and %Treg of CD4 T cells got back to the baseline level by 8 weeks. During the first 3 months after HSCT, CD45RA- Treg exhibited high level of CCR4 and the recovery of this subset was critically delayed in Adult T-cell Leukemia (ATL) patients treated with anti-CCR4 antibody in the peri-transplant period, resulting in the development of acute graft-versus-host diseases. In conclusion, our findings suggest that, not only in the chronic phase but also in the acute phase, the homeostasis of Treg is more susceptible to the post-transplant environment as compared to other lymphocyte subsets. Post-transplant lymphopenia drives aggressive Treg proliferation resulting in the increased percentage of this subset in the very acute phase which may contribute to stabilize the immune recovery. The careful monitoring of Treg from the point of view might provide important information to promote immune tolerance. Disclosures No relevant conflicts of interest to declare.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1520180113 ◽

2016 ◽

Vol 113 (9) ◽

pp. E1286-E1295 ◽

Cited By ~ 73

Author(s):

John F. Ryan ◽

Rachel Hovde ◽

Jacob Glanville ◽

Shu-Chen Lyu ◽

Xuhuai Ji ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Immune Monitoring ◽

T Cell Subsets ◽

Cell Phenotype ◽

Cell Gene Expression ◽

Sustained Success ◽

T Cell Phenotypes ◽

Successful Immunotherapy

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

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The Impact of Exercise Serum on Selected Parameters of CD4+ T Cell Metabolism

Immuno ◽

10.3390/immuno1030008 ◽

2021 ◽

Vol 1 (3) ◽

pp. 119-131

Author(s):

Jana Palmowski ◽

Kristina Gebhardt ◽

Thomas Reichel ◽

Torsten Frech ◽

Robert Ringseis ◽

...

Keyword(s):

T Cells ◽

Oxygen Consumption ◽

T Cell ◽

Real Time ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Autologous Serum ◽

Cell Phenotype ◽

The Impact

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

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CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

Journal of Experimental Medicine ◽

10.1084/jem.20150519 ◽

2015 ◽

Vol 213 (1) ◽

pp. 123-138 ◽

Cited By ~ 68

Author(s):

Arata Takeuchi ◽

Mohamed El Sherif Gadelhaq Badr ◽

Kosuke Miyauchi ◽

Chitose Ishihara ◽

Reiko Onishi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cytotoxic Activity ◽

Cd4 T Cells ◽

Intracellular Signaling ◽

Ectopic Expression ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells ◽

Ifn Γ

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.

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Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus

Journal of Experimental Medicine ◽

10.1084/jem.20121505 ◽

2012 ◽

Vol 209 (12) ◽

pp. 2263-2276 ◽

Cited By ~ 60

Author(s):

Tom M. McCaughtry ◽

Ruth Etzensperger ◽

Amala Alag ◽

Xuguang Tai ◽

Sema Kurtulus ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Conditional Knockout ◽

Cytokine Receptor ◽

T Cell Subsets ◽

Cytotoxic T Cell ◽

Lineage Specification ◽

Class I Mhc ◽

Mhc I

The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Rα or common cytokine receptor γ chain (γc) genes were deleted in thymocytes just before positive selection. We found that γc expression was required to signal the differentiation of MHC class I (MHC-I)–specific thymocytes into CD8+ cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)–specific thymocytes into CD4+ T cells, even into regulatory Foxp3+CD4+ T cells which require γc signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8+ cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8+ T cells expressing Runx3d could arise without γc signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, γc-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I–selected thymocytes into functionally mature T cells.

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The human liver microenvironment shapes the homing and function of CD4+T-cell populations

10.1101/2020.08.03.230953 ◽

2020 ◽

Author(s):

Benjamin G. Wiggins ◽

Laura J. Pallett ◽

Xiaoyan Li ◽

Scott P. Davies ◽

Oliver E. Amin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Human Liver ◽

Memory T Cells ◽

T Cell Subsets ◽

Cell Phenotype ◽

List Type ◽

Cd69 Expression ◽

Resident Memory T Cells

ABSTRACTBackground & AimsTissue-resident memory T cells (TRM) are important immune sentinels that provide efficient in situ immunity. Liver-resident CD8+ TRM have been previously described, and contribute to viral control in persistent hepatotropic infections. However, little is known regarding liver CD4+ TRM cells. Here we profiled resident and non-resident intrahepatic CD4+ T cell subsets, assessing their phenotype, function, differential generation requirements and roles in hepatotropic infection.MethodsLiver tissue was obtained from 173 subjects with (n=109) or without (n=64) hepatic pathology. Multiparametric flow cytometry and immunofluorescence imaging examined T cell phenotype, functionality and location. Liver T cell function was determined after stimulation with anti-CD3/CD28 and PMA/Ionomycin. Co-cultures of blood-derived lymphocytes with hepatocyte cell lines, primary biliary epithelial cells, and precision-cut autologous liver slices were used to investigate the acquisition of liver-resident phenotypes.ResultsCD69 expression delineated two distinct subsets in the human liver. CD69HI cells were identified as CD4+ TRM due to exclusion from the circulation, a residency-associated phenotype (CXCR6+CD49a+S1PR1-PD-1+), restriction to specific liver niches, and ability to produce robust type-1 multifunctional cytokine responses. Conversely, CD69INT were an activated T cell population also found in the peripheral circulation, with a distinct homing profile (CX3CR1+CXCR3+CXCR1+), and a bias towards IL-4 production. Frequencies of CD69INT cells correlated with the degree of fibrosis in chronic hepatitis B virus infection. Interaction with hepatic epithelia was sufficient to generate CD69INT cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HI cells.ConclusionsIntermediate and high CD69 expression demarcates two discrete intrahepatic CD4+ T cell subsets with distinct developmental and functional profiles.Graphical AbstractHighlightsCD69HI (CXCR6+CD49a+S1PR1-PD-1+) are the CD4+ TRM of the human liverHepatic CD69INTCD4+ T-cells are distinct, activated, and recirculation-competentStimulation evokes respective IFN-γ and IL-4 responses in CD69HI and CD69INT cellsCD69INT cell frequencies correlate with worsening fibrosis in chronic HBV patientsLiver slice cultures allow differentiation of CD69INT and CD69HI cells from bloodLay summaryTissue-resident memory T cells (TRM) orchestrate regional immune responses, but much of the biology of liver-resident CD4+ TRM remains unknown. We found high expression of cell-surface protein CD69 defined hepatic CD4+ TRM, while simultaneously uncovering a distinct novel recirculatory CD69INT CD4+ T cell subset. Both subsets displayed unique immune receptor profiles, were functionally skewed towards type-1 and type-2 responses respectively, and had distinct generation requirements, highlighting the potential for differential roles in the immunopathology of chronic liver diseases.

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Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

Journal of Experimental Medicine ◽

10.1084/jem.20160576 ◽

2016 ◽

Vol 213 (11) ◽

pp. 2413-2435 ◽

Cited By ~ 53

Author(s):

Yi Wang ◽

Cindy S. Ma ◽

Yun Ling ◽

Aziz Bousfiha ◽

Yildiz Camcioglu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd4 T Cells ◽

Ex Vivo ◽

Cell Phenotype ◽

Loss Of Function ◽

Inborn Errors

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell–intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.

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Observed Changes in Natural Killer and T cell Phenotypes with Evaluation of Immune Outcome in a Longitudinal Cohort Following Sofosbuvir-Based Therapy for Chronic Hepatitis C Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz223 ◽

2019 ◽

Vol 6 (6) ◽

Cited By ~ 3

Author(s):

Timothy J Stevenson ◽

Youssef Barbour ◽

Brian J McMahon ◽

Lisa Townshend-Bulson ◽

Annette M Hewitt ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Hepatitis C ◽

T Cell ◽

Natural Killer ◽

Chronic Hepatitis C ◽

Nk Cell ◽

Cell Subset ◽

T Cell Subsets ◽

Immune Marker

Abstract Background Chronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown. Methods We examined natural killer (NK) cell, CD4+, and CD8+ T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes. Results We show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8+ T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4+ regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors. Conclusion Our study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.

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Relationship between Multiple Sclerosis-Associated IL2RA Risk Allele Variants and Circulating T Cell Phenotypes in Healthy Genotype-Selected Controls

Cells ◽

10.3390/cells8060634 ◽

2019 ◽

Vol 8 (6) ◽

pp. 634 ◽

Cited By ~ 4

Author(s):

Sophie Buhelt ◽

Helle Bach Søndergaard ◽

Annette Oturai ◽

Henrik Ullum ◽

Marina Rode von Essen ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Interleukin 2 ◽

T Cell Subsets ◽

Multiparameter Flow Cytometry ◽

Risk Genotype ◽

Increased Risk ◽

New Findings

Single nucleotide polymorphisms (SNPs) in or near the IL2RA gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with CD25 expression on T cells ex vivo by multiparameter flow cytometry in paired genotype-selected healthy controls. We observed that MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with expression of CD25 in CD4+ but not CD8+ T cells. In CD4+ T cells, carriers of the risk genotype had a reduced frequency of CD25+ TFH1 cells (p = 0.001) and an increased frequency of CD25+ recent thymic emigrant cells (p = 0.006). Furthermore, carriers of the risk genotype had a reduced surface expression of CD25 in post-thymic expanded CD4+ T cells (CD31−CD45RA+), CD39+ TReg cells and in several non-follicular memory subsets. Our study found novel associations of MS-associated IL2RA SNPs on expression of CD25 in CD4+ T cell subsets. Insight into the associations of MS-associated IL2RA SNPs, as these new findings provide, offers a better understanding of CD25 variation in the immune system and can lead to new insights into how MS-associated SNPs contribute to development of MS.

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