TCR origin and specificity to environmental or self-antigens on distinct antigen-presenting cells determine peripheral Treg cell differentiation
6 affiliations
- 1Department of Immunology, Harvard Medical School, Boston, MA, USA
- 2Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- 3Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- 4Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- 5Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA
- 6Department of Immunology, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected]
Abstract
Peripheral differentiation of regulatory T (pTreg) cells promotes immunological tolerance to obligate non-self, such as food or symbiotic microbes. We examined the relative importance of TCR recognition vs. environmental cues, leveraging CRISPR-based TCR editing of primary T cells with a large TCR panel, assessing pTreg cell differentiation induced by self-, microbial, or dietary antigens. All antigen classes drove stable pTreg cell differentiation, which varied with TCR origin: TCRs derived from Treg cells enabled pTreg cell differentiation more effectively than those from conventional T cells. TCRs recognizing self-, microbial, or dietary antigens elicited distinct pTreg cell phenotypes: Helios⁺, RORγ⁺, or both. Different TCR-antigen pairs established distinct transcriptional programs. These differences traced to the types of antigen-presenting cells (APCs) involved—food-reactive TCRs depended predominantly on RORγ⁺ APCs and self-reactive TCRs depended on conventional dendritic cells. Thus, TCR specificity is a primary determinant of CD4 + T cell fate and phenotype, integrating antigen specificity and presentation context, providing a framework to design TCR-based tolerogenic immunotherapies.
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BibTeX
@article{chi2026origin,
title = {{TCR origin and specificity to environmental or self-antigens on distinct antigen-presenting cells determine peripheral Treg cell differentiation}},
author = {Xinxin Chi and Charlotte H. Wang and Yollanda Franco Parisotto and William A. Nyberg and Vanja Cabric and Adélaïde Gélineau and Yi Cao and David L. Owen and Jonas Ambjörnsson and Diane J. Mathis and Justin Eyquem and Chrysothemis C. Brown and Christophe O. Benoist},
journal = {Immunity},
year = {2026},
month = jul,
doi = {10.1016/j.immuni.2026.07.001},
url = {https://doi.org/10.1016/j.immuni.2026.07.001},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - TCR origin and specificity to environmental or self-antigens on distinct antigen-presenting cells determine peripheral Treg cell differentiation
AU - Xinxin Chi
AU - Charlotte H. Wang
AU - Yollanda Franco Parisotto
AU - William A. Nyberg
AU - Vanja Cabric
AU - Adélaïde Gélineau
AU - Yi Cao
AU - David L. Owen
AU - Jonas Ambjörnsson
AU - Diane J. Mathis
AU - Justin Eyquem
AU - Chrysothemis C. Brown
AU - Christophe O. Benoist
PY - 2026
DA - 2026/07/28
JO - Immunity
DO - 10.1016/j.immuni.2026.07.001
UR - https://doi.org/10.1016/j.immuni.2026.07.001
AB - Peripheral differentiation of regulatory T (pTreg) cells promotes immunological tolerance to obligate non-self, such as food or symbiotic microbes. We examined the relative importance of TCR recognition vs. environmental cues, leveraging CRISPR-based TCR editing of primary T cells with a large TCR panel, assessing pTreg cell differentiation induced by self-, microbial, or dietary antigens. All antigen classes drove stable pTreg cell differentiation, which varied with TCR origin: TCRs derived from Treg cells enabled pTreg cell differentiation more effectively than those from conventional T cells. TCRs recognizing self-, microbial, or dietary antigens elicited distinct pTreg cell phenotypes: Helios⁺, RORγ⁺, or both. Different TCR-antigen pairs established distinct transcriptional programs. These differences traced to the types of antigen-presenting cells (APCs) involved—food-reactive TCRs depended predominantly on RORγ⁺ APCs and self-reactive TCRs depended on conventional dendritic cells. Thus, TCR specificity is a primary determinant of CD4 + T cell fate and phenotype, integrating antigen specificity and presentation context, providing a framework to design TCR-based tolerogenic immunotherapies.
SN - 1074-7613
SN - 1097-4180
ER -