Dataset Information

Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

ABSTRACT: To date many clinical studies aim to increase the number and/or fitness of CD4+CD127lowCD25+ regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4+CD127lowCD25+ TIGIT- T cells distinguished by their elevated IL-6R expression that lacked expression of HELIOS, showed higher CTLA-4 expression, and displayed increased suppressive capacity compared to IL-6RhiTIGIT+ Tregs. IL-6RhiTIGIT- CD127lowCD25+ T cells contained a majority of cells demethylated at FOXP3 and displayed a Th17 transcriptional signature, including RORC (ROR?t) and the capacity of producing both pro- and anti-inflammatory cytokines, such as IL-17, IL-22 and IL-10. We propose that in vivo, in the presence of IL-6-associated inflammation, the suppressive function of CD4+CD127lowCD25+ FOXP3+IL-6RhiTIGIT- T cells is temporarily disarmed allowing further activation of the effector functions and potential pathogenic tissue damage.

SUBMITTER: Ferreira RC

PROVIDER: S-EPMC5471606 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

Ferreira Ricardo C RC Rainbow Daniel B DB Rubio García Arcadio A Pekalski Marcin L ML Porter Linsey L Oliveira João J JJ Waldron-Lynch Frank F Wicker Linda S LS Todd John A JA

Clinical immunology (Orlando, Fla.) 20170309

To date many clinical studies aim to increase the number and/or fitness of CD4+CD127lowCD25+ regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4+CD127lowCD25+ TIGIT- T cells distinguished by their e ...[more]

PMID: 28284938

Similar Datasets

Project description:OBJECTIVE:Despite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127(low) FoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Treg cells are converted into proinflammatory interleukin-17 (IL-17)-producing cells by inflammatory mediators and thereby lose their suppressive function. The aim of this study was to investigate whether activated monocytes, which are potent producers of inflammatory cytokines and are abundantly present in the rheumatic joint, induce proinflammatory cytokine expression in human Treg cells and impair their regulatory function. METHODS:The presence and phenotype of CD4+CD45RO+CD25+CD127(low) T cells (memory Treg cells) and CD14+ monocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with RA were investigated by flow cytometry. Memory Treg cells obtained from healthy control subjects underwent fluorescence-activated cell sorting and then were cocultured with autologous activated monocytes and stimulated with anti-CD3 monoclonal antibodies. Intracellular cytokine expression, phenotype, and function of cells were determined by flow cytometry, enzyme-linked immunosorbent assay, and proliferation assays. RESULTS:In patients with RA, the frequencies of CD4+CD45RO+CD25+CD127(low) Treg cells and activated CD14+ monocytes were higher in SF compared with PB. In vitro-activated monocytes induced an increase in the percentage of IL-17-positive, interferon-? (IFN?)-positive, and tumor necrosis factor ? (TNF?)-positive Treg cells as well as IL-10-positive Treg cells. The observed increase in IL-17-positive and IFN?-positive Treg cells was driven by monocyte-derived IL-1?, IL-6, and TNF? and was mediated by both CD14+CD16- and CD14+CD16+ monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25+FoxP3+CD39+ Treg cell phenotype and showed an enhanced capacity to suppress T cell proliferation and IL-17 production. CONCLUSION:Treg cells exposed to a proinflammatory environment show increased cytokine expression as well as enhanced suppressive activity.

Project description:BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and hepatitis B is one of the commonest causes. T regulatory cells (Tregs) are strong immunomodulators and are likely to play a major role in HCC development. HBV infection is reported to induce expansion of Tregs. We investigated the CD4+CD25+CD127(-ve)FoxP3+ Tregs in HBV-related HCC as compared to non-HBV-HCC.Patients and methodsWhole blood immunophenotyping was analyzed by multicolor flow cytometry in patients with HBV-related HCC (HBV-HCC, n = 17), non-HBV-HCC (n = 22; NASH = 16, alcohol-related = 6), and chronic hepatitis B infection (CHBV; n = 10). Tregs functionality was checked by in vitro suppression assays using CD4+ CD25+ CD127(low) Tregs. Levels of serum alpha-fetoprotein (AFP), expression of FoxP3, IL-10, PD1, TGF-β, and Notch in Tregs, and liver explants were analyzed by flow cytometry, immunohistochemistry, and quantitative RT-PCR.ResultsCD4+CD25+(hi) and Foxp3 expression in CD4+CD25+(hi)CD127(low) was significantly increased (P = 0.04, P = 0.007) in HBVHCC compared to non-HBVHCC and CHBV patients. HBVHCC also showed high IL-10 and TGF-β secreting CD4 + CD25 + (hi)Tregs. The PD1 expression in CD4 + CD25+(hi) was significantly decreased in the HBVHCC than non-HBVHCC. In HBVHCC, AFP levels were significantly high (median 941, range 2-727940) than non-HBVHCC (median 13.5, range 2-18,900). In HBVHCC, patients with high AFP (range; 3982-727940 ng/ml) showed positive correlation with Foxp3 expression in CD4+CD25+(hi) CD127(low) (r = 0.857, P = 0.014). Reduced PD1 expression in HBVHCC also had negative correlation with FOXP3 in CD4+CD25+(hi) CD127(low) (r = -0.78, P = 0.04). However, AFP levels in non-HBVHCC showed negative correlation with (R = -0.67, P = 0.005) with CD4+CD25+(hi) Tregs.ConclusionOur results demonstrate that CD4+ CD25+(hi) Tregs from HBVHCC patients have decreased expression of PD1, resulting in higher IL-10 and TGF-β secretion. Increased suppressive ability of Tregs in HBV-related HCC confers increased anti-tumor suppressive response than in non-HBV-HCC. Modulation of Tregs and PD1 may serve as useful therapeutic targets.

Dataset Information

Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

Publications

Human IL-6R<sup>hi</sup>TIGIT<sup>-</sup> CD4<sup>+</sup>CD127<sup>low</sup>CD25<sup>+</sup> T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets