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.
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