Epigenetic landscape, key transcriptional regulators, and in vivo identification of human Tr1 cells.

Authors

Alma-Martina Cepika, Laura Amaya, Colin Waichler, Mansi Narula, Michelle Mantilla, Benjamin C Thomas, Pauline P Chen, Robert A Freeborn, Mara Pavel-Dinu, Jason Nideffer, Matthew Porteus, Rosa Bacchetta, Fabian Müller, William J Greenleaf, Howard Y Chang, Maria Grazia Roncarolo

Published in

Science advances. Volume 12. Issue 28. Pages eaec6358. Jul 10, 2026. Epub Jul 10, 2026.

Abstract

Type 1 regulatory T (Tr1) cells are CD4⁺ T cells with suppressive function that are induced from conventional T cells exposed to persistent or strong antigens. Human Tr1 cells are understudied; the regulators of their antigen-driven differentiation are unknown, and identifying them in tissues, where antigen interactions occur, is challenging. Here, we conducted a multiomic profiling of human antigen-induced Tr1 cells. Using CRISPR-based functional genomics, we uncovered essential roles of transcription factors IRF4, BATF, and MAF in human Tr1 differentiation, phenotype, and function. We also derived a Tr1 transcriptional signature that detects cells with a Tr1 phenotype in single-cell datasets from patients treated with Tr1 therapy and those with solid tumors. Cross-species analysis confirmed this signature identifies bona fide Tr1 cells induced in vivo in a murine solid tumor model. These findings provide a framework for development of Tr1-based and Tr1-targeting therapies and studies of Tr1 cell biology.

PMID:
42430483
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.

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