Alternatively, IL27, an IL12/IL23 family member, is a negative regulator of Th17 cell differentiation and can prevent inflammatory demyelination in the EAE model [44] . IL27 drives the expansion and differentiation of IL10producing Tr1 cells by inducing the expression of three key molecules: the transcription factor c-MAF, the cytokine IL21, and ICOS. Moreover, IL27-driven c-MAF expression transactivates the production of IL21, which acts as an autocrine growth factor for the expansion and/or maintenance of IL27-induced Tr1 cells. ICOS also promotes IL27-driven Tr1 cells. Each of these elements is essential, because the loss of c-MAF, IL21 signaling, or ICOS reduces the frequency of IL27-induced differentiation of Tr1 cells ( Figure 1 ) [90] . Exacerbation of EAE was demonstrated in IL27-deficient mice, and interestingly, Il27-treated mice had markedly reduced CNS inflammatory infiltration, indicating the downregulation of Th17 phenomena [91] .