IL-17C ameliorates murine acute graft-versus-host disease by promoting regulatory T cell differentiation and maintaining intestinal epithelial barrier functions

Abstract

Abstract Among IL-17 family cytokines, functions of IL-17A, IL-17F, and IL-17E (also named IL-25) are well documented in host defense against infections and inflammatory diseases. Recent studies have demonstrated that IL-17C binds to a unique heterodimeric receptor complex composed of IL-17RA and IL-17RE subunits. IL-17C was reported in the regulation of DSS-induced colitis, experimental autoimmune encephalomyelitis and other inflammatory immune disorders. However, the function of IL-17C in acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. In this study, IL-17C deficiency mice as donors showed a significantly accelerated aGVHD-related mortality compared with wild type donors in a fully MHC-mismatched bone marrow transplantation model (C57BL/6 to BALB/c). We found that the productions of IFN-γ by T cells were significantly increased in spleen, liver, lung as well as intestinal epithelia lymphocytes with IL-17C deficient donors. Furthermore, a reduction of FoxP3+ regulatory T cell population was observed with IL-17C−/− donors. In vitro studies showed that the percentage of Treg cells were decreased in IL-17C−/− splenocytes in a Treg polarizing condition compared with WT splenocytes. Moreover, the expression of tight junction protein occludin was decreased with IL-17C−/− donors when compared with WT controls. In summary, IL-17C protects against aGVHD by possibly promoting Treg differentiation and maintaining intestinal barrier functions. Further studies are required to explore detailed mechanisms of its action and its potential therapeutic applications for clinical prevention and treatment of aGVHD.