We found that NFIL3 deficiency resulted in reduced Tim-3 and IL-10 expression in all conditions, suggesting that NFIL3 is critical for the expression of both Tim-3 and IL-10 (Fig

We found that NFIL3 deficiency resulted in reduced Tim-3 and IL-10 expression in all conditions, suggesting that NFIL3 is critical for the expression of both Tim-3 and IL-10 (Fig. a key regulator of the exhausted antigen-specific CD4+ and CD8+ T cells that arise in both humans and mice during chronic viral infections such as HIV, HCV, HBV and LCMV 3C5 and in cancer 6C8. Exhaustion refers to a state of dysfunction that typically arises in a hierarchical fashion whereby effector T cells first lose the ability to proliferate and be cytotoxic in response to antigen stimulation. This is then followed by the loss of IL-2 secretion, which is usually followed by a gradual loss of TNF and IFN- and increased production BGLAP of the immunosuppressive cytokine IL-10. Accordingly, exhausted T cells pose a significant barrier to the induction of productive anti-viral or anti-tumor immunity. In contrast, one could envisage that in autoimmune diseases, the induction of T cell exhaustion would be beneficial. While primarily RO4927350 studied in CD8+ T cells, exhaustion also occurs in CD4+ T cells 3. Exhausted T cells are characterized by RO4927350 their sustained expression of inhibitory receptors. Programmed death-1 (PD-1) was the first such molecule to be identified; its inhibitory function is essential for the induction of T cell exhaustion during chronic LCMV contamination in mice, and during chronic HIV contamination in humans 9C12. It is now appreciated that co-expression of PD-1 with other inhibitory receptors, such as Tim-3, contributes to the induction of T cell exhaustion and as such defines T cells with more deeply exhausted phenotype 5. Importantly, simultaneous blockade of the Tim-3 and PD-1 signaling pathways restores CTL function and cytokine production, while blockade of the PD-1 pathway alone is usually less effective. Thus, targeting Tim-3 on exhausted T cells provides a potential therapeutic avenue for treating multiple chronic viral infections and cancers. On the other hand, increasing Tim-3 expression would be beneficial for autoimmunity as reduced amounts of Tim-3 expression have been associated with a RO4927350 number of human autoimmune diseases 13. In spite of the increasing data linking Tim-3 to the suppression of T cell immunity, little is known about the signals by which its expression is usually induced on T cells. It was therefore important to identify the cytokines and pathways that induce the expression of this inhibitory molecule. In this study, we demonstrate that IL-27, an immunosuppressive cytokine, is usually a potent inducer of Tim-3 expression on T cells. IL-27 RO4927350 strongly induces the expression of the transcription factor nuclear factor, interleukin 3 regulated (NFIL3), which cooperates with T-bet, to induce the expression of Tim-3 and IL-10. In addition, IL-27-conditioned Th1 cells exhibited poor effector function and are poor mediators of intestinal inflammation in an NFIL3-dependent manner. We RO4927350 show that IL-27 signaling is required for the induction of Tim-3+ exhausted T cells and promotion of tumor growth. Thus, we have uncovered that an IL-27/NFIL3 signaling axis drives inhibition of effector T cells via the induction of Tim-3, IL-10, and dysfunctional T cell phenotype. RESULTS IL-27 is usually a potent inducer of Tim-3 in na?ve CD4+ T cells Our previous study indicated that T-bet is usually more functionally critical than STAT4 in the induction of Tim-3 expression on Th1 cells 14. The modest reduction of Tim-3 expression in IL-12-polarized Th1 cells indicated that Tim-3 expression is not completely dependent on IL-12 signaling. To further explore other.