Epigenetic landscape, key transcriptional regulators, and in vivo identification of human Tr1 cells [ATAC-seq]

Type 1 regulatory T (Tr1) cells are CD4+ T cells with immunoregulatory function, which are induced from mature peripheral CD4+ T cells in response to persistent extra-thymic antigens. The role of human Tr1 cells in disease is not completely understood, because transcription factors that regulate their antigen-driven differentiation are not known, and there is lack of consensus on how to best identify them in the tissue, where antigen interactions occur. Here, we leveraged comprehensive bulk and single-cell (sc) transcriptomic, epigenomic, and TCR repertoire profiling of human antigen-induced Tr1 cells, complemented with CRISPR-based functional genomics, to uncover the role of transcription factors IRF4, BATF and MAF in human Tr1 cell differentiation and function. In addition, we identify a Tr1 cell transcriptional signature that can reveal Tr1-like cells in sc-RNA-seq datasets of peripheral blood CD4+ T cells of patients treated with Tr1 therapy, and within tumor-resident CD4+ T cells in patients with clear-cell renal cell carcinoma, triple-negative breast cancer, and colorectal cancer. These data enable further development of Tr1 therapies and Tr1-targeting treatments, and provide new insights into human Tr1 cell biology.