Rap1 prevents colitogenic Th17 cell expansion and facilitates Treg cell differentiation and distal TCR signaling

Sayaka Ishihara,Noriyuki Fujikado,Tsuyoshi Sato,Shinji Fukuda,Koko Katagiri,Hiromitsu Yamamoto,Takayuki Yoshimoto,Haruka Miyazaki

doi:10.1038/s42003-022-03129-x

Abstract

T-cell-specific Rap1 deletion causes spontaneous colitis in mice. In the present study, we revealed that Rap1 deficiency in T cells impaired the preceding induction of intestinal RORγt+ 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 microbiota-dependent manner, and the inhibition of IL-17A production prevented the development of colitis. In the LILP of Rap1KO mice, RORγt+ Treg cells were scarcely induced by 4 weeks of age. 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. 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 as well as Th1 and Th2 cells was lesser than that of wild-type cells. Rap1-deficient naïve CD4+ T cells were found to exhibit the defective nuclear translocation of NFAT and formation of actin foci in response to TCR engagement. These data suggest that Rap1 amplifies the TCR signaling required for Treg-mediated control of intestinal colitogenic Th17 responses.

Highlights

T-cell-specific Rap[1] deletion causes spontaneous colitis in mice
Peripheral Treg cells arise from naïve CD4+Forkhead box P3 (Foxp3)− conventional T cells (CD4+ cells) at the periphery upon antigen stimulation with an appropriate combination of cytokines such as IL-2 and TGFβ13,14. pTreg are mostly present in the intestine, primarily because of the abundant expression of TGFβ and retinoic acid, and are thought to be important in the establishment of tolerance to commensal bacteria at mucosal sites[15–17]
IL-17A+ cells and IL-17A+IFNγ+ cells increased in the mesenteric lymph nodes and blood of Rap1KO mice (Fig. 1b)

Summary

Introduction

T-cell-specific Rap[1] deletion causes spontaneous colitis in mice. In the present study, we revealed that Rap[1] deficiency in T cells impaired the preceding induction of intestinal RORγt+ 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 microbiota-dependent manner, and the inhibition of IL-17A production prevented the development of colitis. Rap1-deficient naïve CD4+ T cells were found to exhibit the defective nuclear translocation of NFAT and formation of actin foci in response to TCR engagement. These data suggest that Rap[1] amplifies the TCR signaling required for Treg-mediated control of intestinal colitogenic Th17 responses. Regulatory T (Treg) cells suppress excess immunity against self-antigen and commensal bacteria-derived antigens[5,6] These cells are characterized by the expression of the transcription factor Forkhead box P3 (Foxp3), which plays crucial roles in the differentiation, maintenance, and function of Treg cells[7,8]. RORγt+ Treg cell deficiency exacerbates colitogenic Th17 cell differentiation and promotes colonic inflammation[21]

Methods

Results

Conclusion