Intestinal Cdc1 Drive Cross-Tolerance To Epithelial-Derived Antigen Via Induction Of Foxp3(+) Cd8(+) T-Regs

Although CD8(+) T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and suppressive function of FoxP3(+)CD8(+) T cells. FoxP3(+)CD8(+) T-reg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1-derived PD-L1, TGF beta, and retinoic acid contributed to the generation of gut-tropic CCR9(+)CD103(+)FoxP3(+)CD8(+) T-regs. Last, CD103-deficient CD8(+) T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3(+) CD8(+) T-reg function. Our results describe a role for FoxP3(+)CD8(+) T-regs in cross-tolerance in the intestine for which development requires intestinal cDC1.