IL-27 also exacerbates inflammatory responses by restraining inducible Treg development11

IL-27 also exacerbates inflammatory responses by restraining inducible Treg development11. In the context of intestinal inflammation, the roles of IL-27 again remain controversial. cytokines in APCs. infection, emphasizing the Th1-promoting role of IL-276. On the other hand, IL-27 also exhibits immunosuppressive properties. IL-27R?/? mice infected with fail to downregulate immune responses, developing lethal T cell mediated immune responses6. Particularly interesting is the immunosuppressive functions of IL-27 in the Amifampridine context of Th17 immunity. IL-27R?/? mice are highly susceptible to the induction of Th17 mediated neuroinflammation8. One proposed mechanism is that IL-27 induces IL-10 production by T cells9. IL-27 also modulates regulatory T cell (Treg) functions. IL-27 promotes the development Amifampridine of Treg cells that control inflammatory immunity at the site of inflammation10. IL-27 also exacerbates inflammatory responses by restraining inducible Treg development11. In the context of intestinal inflammation, the roles of IL-27 again remain controversial. Immunodeficient hosts transferred with IL-27R?/? CD4 T cells develop attenuated colitis, which has been attributed to increased inducible Foxp3+ Treg conversion11. The fact that and mRNA expression is upregulated in biopsy samples of active IBD patients further supports the notion that IL-27 may play a Amifampridine crucial proinflammatory role12. On the other hand, a recent genome wide association study has identified five new regions associated with JAB early onset IBD susceptibility, including IL-2713. In this study, IL-27 expression in patients with early-onset Crohns disease was significantly lower than that in healthy control13. In the DSS model of colitis, IL-27 can be either protective or pathogenic14, 15. With regard to IL-27 action on non-T cells, IL-27 upregulates MHC and TLR4 expression in human monocytes, leading to increased production of IL-6 and IL-1 upon LPS stimulation infection model18. The roles for IL-27 in non-T cells remain unclear. Here we report that IL-27 acting on APCs plays a crucial role in optimizing Th17 differentiation by augmenting production of Th17 promoting cytokines. IL-27R?/? lymphopenic hosts were completely protected from T cell-mediated colitis, while IL-27R+/+ lymphopenic mice develop fulminant inflammation in the colon. T cell differentiation into Th17 lineage effector cells was selectively impaired in mice without IL-27R. APCs, primarily macrophages and dendritic cells (DCs), were defective in producing Th17 promoting cytokines, IL-1 and IL-6. Therefore, IL-27, acting on APCs, plays an important proinflammatory function in supporting Th17 differentiation was markedly decreased in Amifampridine IL-27R?/? TCR?/? mice (Figure 1d). Expression of IL-12 subunits, and and was markedly decreased in the absence of IL-27 signaling (Figure 2e), further supporting the lack of Th17 differentiation. The expression of IL-23 was similar between the groups, suggesting that impaired Th17 differentiation was not due to differential expression of IL-23 (Figure 2e). expression was not found (data not shown). expression was similar between the groups; therefore, defective Th17 differentiation in IL-27R?/? TCR?/? recipients was not due to elevated production of anti inflammatory cytokines such as IL-10 (not shown). Collectively, these results demonstrate that the IL-27R deficiency in recipient-derived cells plays a key role particularly in Th17 differentiation possibly by controlling the production of Th17-promoting cytokines. Open in a separate window Figure 2 CD4 T cells transferred into lymphopenic TCR?/? mice deficient in IL-27R fail to differentiate into IL-17 producing CD4 T cells2.5105 na?ve CD4 T cells were transferred into TCR?/? or IL-27R?/? TCR?/? mice. All data is from 7 days after transfer. (a) Frequency of the donor CD4 T cell cytokine production after PMA/Ionomycin stimulation from the mLN. (b) Donor cell recovery from the mLN. (c) Number of cytokine producing donor CD4 from the mLN. (d) T cell differentiation profiles in IL-27R?/? TCR?/? recipients after anti IFN mAb treatment. (e) Gene expression from the mLN tissue. All values were normalized to GAPDH expression. Data shown are representatives of 2-3 independent experiments, N=3-6. Error bars indicate mean SEM. *, p<0.05; **, p< 0.01; ***, p<0.001. Non-colitogenic cells generated in IL-27R?/?TCR?/? recipients still express.