Research ArticleAUTOIMMUNITY

Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3+CD8+ Tregs

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Science Immunology  04 Jun 2021:
Vol. 6, Issue 60, eabd3774
DOI: 10.1126/sciimmunol.abd3774

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A tolerance tale

Peripheral tolerance prevents autoimmune responses mediated by autoreactive T cells, and conventional dendritic cells (cDCs) can present tissue-specific antigen (TSA) and induce anergy and deletion of autoreactive T cells in local lymph nodes. Here, Joeris et al. examined the role of intestinal cDC1 presenting TSA derived from intestinal epithelial cells (IECs) in driving cross-tolerance of CD8+ T cells. cDC1 mediated peripheral tolerance by converting naïve CD8+ T cells to intestine-homing CCR9+ FoxP3+CD8+ Tregs, which involved programmed death ligand 1 (PD-L1), retinoic acid (RA), and transforming growth factor β (TGFβ) derived from intestinal cDC1. CD103 expression was needed for the tolerogenic function of these FoxP3+CD8+ Tregs. These findings highlight a role for cDC1-mediated induction of FoxP3+CD8+ Tregs in cross-tolerance to TSA in the intestine.


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+ Treg 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+ Tregs. Last, CD103-deficient CD8+ T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3+CD8+ Treg function. Our results describe a role for FoxP3+CD8+ Tregs in cross-tolerance in the intestine for which development requires intestinal cDC1.

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