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.

尽管 CD8 ⁺ T 细胞对组织特异性抗原 (TSA) 的耐受性对于宿主稳态至关重要，但外周交叉耐受性的潜在机制以及它们是否可能在组织部位之间存在差异仍有待完全阐明。在这里，我们证明了对肠上皮细胞 (IEC) 衍生抗原的外周交叉耐受性涉及 FoxP3 ⁺ CD8 ⁺ T 细胞的产生和抑制功能。FoxP3 ⁺ CD8 ⁺ T _reg的生成依赖于肠道 cDC1，其缺失导致耐受性中断和上皮破坏。机制上，肠道 cDC1 衍生的 PD-L1、TGFβ 和视黄酸有助于产生肠道嗜性 CCR9 ⁺CD103 ⁺ FoxP3 ⁺ CD8 ⁺ T_调节器。最后，CD103 缺陷型 CD8 ⁺ T 细胞在体内缺乏致耐受性活性，表明 CD103 在 FoxP3 ⁺ CD8 ⁺ T _reg功能中的作用。我们的结果描述了 FoxP3 ⁺ CD8 ⁺ T _regs在肠道交叉耐受中的作用，其发育需要肠道 cDC1。