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

Joeris, Thorsten LU ; Gomez-Casado, Cristina LU ; Holmkvist, Petra LU ; Tavernier, Simon J ; Silva-Sanchez, Aaron ; Klotz, Luisa ; Randall, Troy D ; Mowat, Allan M LU ; Kotarsky, Knut LU and Malissen, Bernard , et al. (2021) In Science Immunology 6(60).
Abstract

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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Immunology
volume
6
issue
60
article number
eabd3774
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:34088744
  • scopus:85107535723
ISSN
2470-9468
DOI
10.1126/sciimmunol.abd3774
language
English
LU publication?
yes
id
dd55cc66-71f2-428e-a7e6-fe9742c2a17b
date added to LUP
2021-06-11 15:34:20
date last changed
2024-06-16 15:00:07
@article{dd55cc66-71f2-428e-a7e6-fe9742c2a17b,
  abstract     = {{<p>Although CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> T cells. FoxP3<sup>+</sup>CD8<sup>+</sup> T<sub>reg</sub> 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<sup>+</sup>CD103<sup>+</sup>FoxP3<sup>+</sup>CD8<sup>+</sup> T<sub>regs</sub>. Last, CD103-deficient CD8<sup>+</sup> T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3<sup>+</sup>CD8<sup>+</sup> T<sub>reg</sub> function. Our results describe a role for FoxP3<sup>+</sup>CD8<sup>+</sup> T<sub>regs</sub> in cross-tolerance in the intestine for which development requires intestinal cDC1.</p>}},
  author       = {{Joeris, Thorsten and Gomez-Casado, Cristina and Holmkvist, Petra and Tavernier, Simon J and Silva-Sanchez, Aaron and Klotz, Luisa and Randall, Troy D and Mowat, Allan M and Kotarsky, Knut and Malissen, Bernard and Agace, William W}},
  issn         = {{2470-9468}},
  language     = {{eng}},
  number       = {{60}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Immunology}},
  title        = {{Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3+CD8+ Tregs}},
  url          = {{http://dx.doi.org/10.1126/sciimmunol.abd3774}},
  doi          = {{10.1126/sciimmunol.abd3774}},
  volume       = {{6}},
  year         = {{2021}},
}