Role of Rap1 in preventing colitogenic Th17 cell expansion and in Treg cell differentiation and distal TCR signaling

T-cell-specific Rap1 deletion causes spontaneous colitis in mice. We revealed that Rap1 deficiency in T cells impaired the induction of intestinal ROR-gamma-t+ Treg cells. In the large intestinal lamina propria (LILP) of T-cell-specific Rap1- knockout mice (Rap1KO mice), Th17 cells were found to increase in a microbiotadependent manner, and the inhibition of IL-17A production prevented the development of colitis. When cultured under each polarizing condition, Rap1-deficient naïve CD4+ T cells did not show biased differentiation into Th17 cells; their differentiation into Treg cells was lesser than that of wild-type cells. The expression of CTLA-4 on Rap1-deficient Treg cells was reduced and the expression of CD80 and CD86 on dendritic cells was consequently elevated in Rap1KO mice. Rap1-deficient naïve CD4+ T cells were found to exhibit impaired TCR-dependent CTLA-4 induction, and the defective nuclear translocation of NFAT and formation of actin foci in response to TCR engagement. These data suggest that Rap1 facilitates the distal TCR signaling required for the optimal differentiation and suppressive functions of Treg cells.