Accumulation of T regulatory (Treg) cells within the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) is essential for the resolution of disease. CNS Treg cells have been shown to uniformly express the Th1-associated molecules, T-bet and CXCR3. Here, we report that the expression of T-bet is not required for the function of these Treg within the CNS. Using mice that lacked T-bet expression specifically within the Treg compartment, we demonstrate that there was no deficit in Treg recruitment into the CNS during EAE and no difference in the resolution of disease compared to control mice. T-bet deficiency did not impact on the in vitro suppressive capacity of Treg. Transfer of T-bet-deficient Treg was able to suppress clinical signs of either EAE or colitis. These observations demonstrate that, although Treg can acquire characteristics associated with pathogenic T effector cells, this process is not necessarily required for their suppressive capacity and the resolution of autoimmune inflammation.

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Mice lacking IL-6 are resistant to autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), which is driven by central nervous system (CNS)-reactive CD4+ T cells. There are multiple cellular sources of IL-6, but the critical source in EAE has been uncertain. Using cell-specific IL-6-deficiency in models of EAE induced by active immunization, passive transfer, T cell-transfer and dendritic cell (DC)-transfer, we show that neither the pathogenic T cells, nor CNS-resident cells are required to produce IL-6. Instead, the requirement for IL-6 was restricted to the early stages of T cell activation and was entirely controlled by DC-derived IL-6. This reflected the loss of IL-6 receptor expression by T cells over time. These data explain why blockade of the IL-6 receptor only achieves protection against EAE if used at the time of T cell priming. The implications for therapeutic manipulation of IL-6-signaling in human T cell-driven autoimmune conditions are considered.