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Non-classical CD4+CD49b+ regulatory T cells as a better alternative to conventional CD4+CD25+ T cells to dampen arthritis severity

ABSTRACT: Regulatory T (Treg) cells actively control pathological immune responses and immunotherapeutic strategies triggering an increase in the number and/or the function of endogenous Treg cells emerge as a promising therapeutic strategy in autoimmune diseases to restore tolerance. A remarkable heterogeneity in peripheral Treg cells has been evidenced and underscored the need to better characterize them and compare their suppressive function to determine which Treg subset will be optimally suitable for a given clinical situation. We demonstrated that repetitive injections of immature dendritic cells (DC) expand FoxP3-negative CD49b+ Treg cells that display an effector memory phenotype. Transcriptome analysis of ex-vivo isolated Treg-expanded by DC injections contains multiple transcripts of the canonical Treg signature shared mainly by CD25+ but also by other Treg subphenotypes. We provided an in-depth characterization of the CD49b+ Treg cells phenotype underscoring their similarities with CD25+ Treg cells and highlighting some specific expression pattern for several markers including LAG3, KLRG1, CD103, ICOS, CTLA-4 and GZB. Comparison of their suppressive mechanism in vitro and in vivo with that of FoxP3-positive Treg cells provide evidence of their potent suppressive activity in vivo, partly dependent on IL-10 secretion. Altogether our results underscore the therapeutic potential of IL-10 secreting CD49b+ Treg cells in arthritis and strongly suggest that expression of several canonical markers and suppressive function could be FoxP3-independent

ORGANISM(S): Mus musculus

PROVIDER: GSE68621 | GEO | 2015/12/10

SECONDARY ACCESSION(S): PRJNA283217

REPOSITORIES: GEO

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Project description:The epigenetic regulation of transcription factor genes is critical for T cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and required for stable expression of FOXP3 and suppressive function. We analyzed the impact of hypomethylating agents 5-Aza-2`-deoxycytidine and Epigallocatechin-3-gallate (EGCG) on human CD4+CD25- T for generating Treg cell specific DNA methylation pattern within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage specifying transcription factors of the major T cell lineages and their leading cytokines, functional properties and global transcriptome changes were analyzed. 5-Aza-2`-deoxycytidine induced FOXP3-TSDR methylation and expression of Treg cell specific genes FOXP3 and LRRC32. Proliferation of 5-Aza-2Â´deoxycytidine treated cells was reduced, but they did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of Th1 and Th17 cells were induced. EGCG induced global DNA hypomethylation to a lower degree than 5-Aza-2Â´deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg cell specific genes. Both DNMT inhibitors did not induce full functional human Treg cells. Although 5-Aza-2`-deoxycytidine treated cells phenotypically appeared to be Treg cells, they did not suppress proliferation of responder cells, which is an essential capability to be used in Treg cell transfer therapy. In this study we analyze the potency of the two hypomethylating agents 5-Aza-2`-deoxycytidine (5-Aza-dC) and Epigallocatechin-3-gallate (EGCG) for in vitro induction of functional Treg cell cells through generation of a specific methylation pattern within FOXP3-TSDR. We analyzed the expression of Treg cell specific genes and for their functional properties from CD4+CD25- T cells. 5-Aza-dC is a derivative of 5-Azacytidine. Both substances are inhibitors of DNA methyltransferases (DNMTs) and used for therapy of patients with myelodysplastic syndrome and acute myeloid leukaemia. In these patients, 5-Azacytidine has been reported to augment regulatory T cell expansion in blood. EGCG is the most abundant catechin of green tea and has been reported to have cardio protective, anti-cancer, anti-infective properties and protective effects on autoimmune diseases. EGCG has also been described as a potent inhibitor of DNMTs and to induce Foxp3 in Jurkat T cell line.

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Non-classical CD4+CD49b+ regulatory T cells as a better alternative to conventional CD4+CD25+ T cells to dampen arthritis severity

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