Decoding Peripheral Tolerance: TCR Rules for pTreg differentiation in the Gut

Chi, X.; Wang, C. H.; Parisotto, Y. F.; Nyberg, W. A.; Cabric, V.; Gelineau, A.; Cao, Y.; Owen, D. L.; Ambjörnsson, J.; Mathis, D.; Eyquem, J.; Brown, C. C.; Benoist, C.

doi:10.1101/2025.10.20.683415

bioRxiv · 10.1101/2025.10.20.683415

Decoding Peripheral Tolerance: TCR Rules for pTreg differentiation in the Gut

Chi, X.·Wang, C. H.·Parisotto, Y. F.·Nyberg, W. A.·Cabric, V.·Gelineau, A.·Cao, Y.·Owen, D. L.·Ambjörnsson, J.·Mathis, D.·Eyquem, J.·Brown, C. C.·Benoist, C.

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Abstract

Peripheral differentiation of regulatory T cells (pTregs) promoted by foreign antigens encountered in barrier tissues is considered a unique contributor to immunological tolerance to obligate non-self, like food or symbiotic microbes. The relative importance of adaptive recognition via the T cell receptor (TCR) vs environmental small-molecule or neuroimmune cues, is poorly understood. We leverage CRISPR-based TCR editing to perform in primary T cells in vivo, with a large panel of TCRs, a screen to assess pTreg differentiation induced by self, microbial, or dietary antigens. All antigen classes drive pTreg differentiation, which varies with the origin of the TCR: TCRs derived from Tregs enable pTreg differentiation much more effectively than those from Tconv. TCRs recognizing self, microbial, or dietary antigens elicit distinct pTreg phenotypes, Helios, ROR{gamma}, or both. Mechanistically, these trace to different types of antigen-presenting-cell involved. That Treg-derived TCRs preferentially drive tolerogenic fate speaks to preferential drivers of tolerogenic therapy.

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Chi, X., Wang, C. H., Parisotto, Y. F., Nyberg, W. A., Cabric, V., Gelineau, A., Cao, Y., Owen, D. L., Ambjörnsson, J., Mathis, D., Eyquem, J., Brown, C. C., Benoist, C.. 2025-10-20. Decoding Peripheral Tolerance: TCR Rules for pTreg differentiation in the Gut. https://doi.org/10.1101/2025.10.20.683415

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