Epigenetic landscape, key transcriptional regulators, and in vivo identification of human Tr1 cells
- 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
2026-07-10
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.