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“Foxp3+ T regulatory (Treg) cells can be induced to produce interleukin (IL)-17 by in vitro exposure to proinflammatory cytokines, selleck chemicals llc drawing into question their functional stability at sites of inflammation.

Unlike their splenic counterparts, Treg cells from the inflamed central nervous system (CNS-Treg cells) during EAE resisted conversion to IL-17 production when exposed to IL-6. We show that the highly activated phenotype of CNS-Treg cells includes elevated expression of the Th1-associated molecules CXCR3 and T-bet, but reduced expression of the IL-6 receptor α chain (CD126) and the signaling chain gp130. We found a lack of IL-6 receptor on all CNS CD4+ T cells, which was reflected by an absence of both classical and trans-IL-6 signaling in CNS CD4+ buy GSK2126458 cells, compared with their splenic counterparts. We propose that extinguished responsiveness to IL-6 (via down-regulation of CD126 and gp130) stabilizes the regulatory phenotype of activated Treg cells at sites of autoimmune inflammation. Foxp3+ Treg

cells are primary mediators of peripheral tolerance and have shown therapeutic potential in models of organ-specific autoimmune disease [[1]]. However, Treg cells have also been reported to produce interleukin (IL)-17 when stimulated in vitro in the presence of inflammatory cytokines [[2, 3]], suggesting that Treg cells can adapt to an inflammatory environment by acquiring certain effector characteristics. Here, we tested whether Treg cells isolated from a site of autoimmune inflammation could be driven toward an effector phenotype. We used the experimental autoimmune stiripentol encephalomyelitis (EAE) model wherein Foxp3+ Treg cells accumulate in the inflamed central nervous system (CNS). Unlike their splenic counterparts, CNS-Treg cells resisted conversion into an IL-17-secreting population. This resistance was attributable to a reduction in IL-6 responsiveness due to the fact that

CNS-Treg cells lacked expression of both chains of the IL-6 receptor, CD126, and gp130. We therefore reveal a key mechanism allowing Treg cells that are active in sites of inflammation to maintain a commitment to an antiinflammatory role. We fluorescence-activated cell sorter (FACS)-sorted Treg (GFP+) and non-Treg (GFP−) CD4+ cells from the spleen and CNS of Foxp3-GFP mice with EAE and assessed their cytokine production profile. CNS Foxp3− T cells showed production of IL-2 and a broad range of effector cytokines (IL-4, IL-5, IL-17, IFN-γ, TNF-α, and GM-CSF) in response to anti-CD3+anti-CD28 stimulation. In contrast, Foxp3+ cells from the CNS showed no production of these effector cytokines, with only low-level production of IL-10 being evident (Fig. 1A). We next tested FACS-sorted GFP+ (Foxp3+) CNS-Treg cells under in vitro exposure to a well-characterized IL-17-promoting cocktail.