期刊
SCIENCE IMMUNOLOGY
卷 6, 期 60, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abd3774
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资金
- Danish Research Council (Sapere Aude III) [1331-00136B]
- Lundbeck Foundation, Denmark [R155-2014-4184]
- Swedish Medical Research Council [2017-02072]
- Swedish Cancerfonden [18 0598]
- IngaBritt and Arne Lundbergs Foundation
- Prof. Nanna Svartz Fond
- Royal Physiographic Society of Lund
- Anna-Greta Crafoord Foundation
- Carl Tryggers Foundation
- Ruth and Richard Julins Foundation
- Swedish Research Council [2017-02072] Funding Source: Swedish Research Council
The study revealed that peripheral cross-tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and suppressive function of FoxP3(+)CD8(+) T cells, which requires the involvement of intestinal cDC1. Factors such as PD-L1, TGF beta, and retinoic acid contribute to the generation of gut-tropic CCR9(+)CD103(+)FoxP3(+)CD8(+) T-regs. CD103 deficiency in CD8(+) T cells results in a lack of tolerogenic activity in vivo.
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, TGF beta, 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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