IL-25 promotes the function of CD4+CD25 + T regulatory cells and prolongs skin-graft survival in murine models

• IL-25 knockout mice exhibited decreased Foxp3 expression in CD4+ T cells, and enhanced inflammatory cytokine secretion in skin allograft recipients.
• IL-25 deficiency decreased both Foxp3 expression and functions of iTregs in vitro.
• Adoptive transfer of WT Tregs exhibited greater functions than IL-25–/– Tregs in mouse models of allograft immunological rejection.
• IL-25 could promote phosphorylation of NFAT2, thus may preserve Foxp3 expression and Treg function.

Interleukin (IL)-25, also known as IL-17E, belongs to the IL-17 family of cytokines. Unlike other IL-17 family members, IL-25 promotes Th2-type immune responses, stimulating IL-4, IL-5, and IL-13 production. Here, we employed murine models of skin graft to explore the role of IL-25 in suppression of graft rejection. We found that IL-25 expression is increased during allograft rejection, and allograft rejection was enhanced in IL-25 KO mice. IL-25 KO was associated with down-regulation of Foxp3 expression in CD4+ T cells. Further, while adoptive transfer of WT regulatory T cells (Tregs) protected against allograft rejection, adoptive transfer of IL-25 deficient Tregs failed to protect against allograft rejection. Exogenous IL-25 restored Foxp3 expression and Treg function in vitro. Moreover, IL-25 promoted phosphorylation of NFAT2. Thus, IL-25 may enhance Treg function by up-regulating NFAT2 phosphorylation. Our findings suggest that IL-25 can sustain Foxp3 expression, enhance the suppressive function of Tregs, and prolong skin-graft survival.