Cumulatively, these data therefore suggest that the inability to respond to IL-6 is not a direct consequence of T-bet expression by Treg cells.

Exposure to retinoic acid (RA) promotes resistance to IL-17 production in nTreg via down-regulation of CD126 expression [[17]]. RA is produced at sites of inflammation [[18]] and whether such an effect in the inflamed CNS might maintain the IL-6-insensitive phenotype of CNS T cells is worthy of further investigation. Recent fate-mapping studies showed that the majority of CD4+ effector T cells infiltrating the CNS during EAE have, at some point, produced IL-17 [[19, 20]]. Unlike their Foxp3− counterparts however, CNS-derived Foxp3+ cells showed no history of IL-17 expression [[20]]. We can therefore conclude that the KU-60019 cost inflammatory environment within the CNS fails to induce IL-17 production by the infiltrating Foxp3+ T cells and, from our data here, that these cells resist conversion, even when experimentally Enzalutamide concentration challenged under potent IL-17-inducing conditions that work on Treg cells taken from noninflamed sites. Besides inducing IL-17 production in Treg

cells, several inflammatory cytokines, including IL-6, can also render effector T cells resistant to suppression as measured using in vitro assays [[5, 21]]. On this point, our data on the insensitivity of CNS GFP− cells to IL-6 are noteworthy, and would exclude such a function of IL-6 within the CNS, at least one that acted directly on T cells. We demonstrate that the response of CNS-Treg cells to inflammatory cytokines cannot

be predicted accurately from the behavior of peripheral Treg cells taken from the same individual. This has implications for human studies that sample Treg cells from the circulation, such as the recent description of elevated IFN-γ production by peripheral blood Foxp3+ cells from multiple sclerosis (MS) patients [[22]]. The prediction from our study would be that CNS-Treg cells in MS might maintain suppressive, rather than effector function. Furthermore, concerns that Treg cells that have been manipulated therapeutically might develop unwanted effector function (based on in vitro observation using “naïve” Treg cells) might be overstated. Perhaps the most interesting MG-132 molecular weight feature of our current comparison of CNS and peripheral T cells is the apparent loss of gp130 from all CD4+ cells in the CNS, given that gp130 is the signaling unit for other cytokines, including IL-11, IL-27, and leukemia inhibitory factor (reviewed in [[7]]). The down-regulation of gp130 should render CNS T cells insensitive to the effects of these cytokines also. Spatial and temporal variation in the expression of cytokine receptors therefore offers a fundamental means of controlling effector and Treg-cell function at different stages of an inflammatory immune response. This possibility certainly warrants further study. Foxp3-GFP mice [[23]] and Foxp3.