Intestinal cDC1 Drive Cross-Tolerance to Epithelial-Derived Antigen Via Induction of FoxP3+CD8+ Tregs

Abstract

While CD8+ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the underlying mechanisms of peripheral cross-tolerance and whether they may differ between tissue sites remains to be fully elucidated. Here we demonstrate that peripheral cross tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and local suppressive function of FoxP3+CD8+ T cells. FoxP3+CD8+T_reg cell generation was dependent on intestinal cDC1 whose absence lead to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1 derived PD-L1, TGFb and retinoic acid contributed to the generation of ‘gut tropic’ CCR9+CD103+FoxP3+CD8+ T_reg cells. Moreover, CD103 deficient FoxP3+CD8+ T_reg cells lacked tolerogenic activity in vivo, indicating an important local role for CD103 and its IEC ligand E-cadherin in FoxP3+CD8+T function. In conclusion, our results describe an important role for FoxP3+CD8+T cells in cross-tolerance in the intestine whose development requires intestinal cDC1.

Keywords: intestine, cross-tolerance, Treg, FoxP3+CD8+ T cells, intestinal epithelial cells, self-antigen, CD103, TGF bet, PD-L1, autoimmunity, retinoid acid, CTL