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, TGFβ, 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.