BACH2 regulates diversification of regulatory and proinflammatory chromatin states in T17 cells.

Interleukin-17 (IL-17)-producing helper T (T17) cells are heterogenous and consist of nonpathogenic T17 (npT17) cells that contribute to tissue homeostasis and pathogenic T17 (pT17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T17 heterogeneity and discover substantial differences in the chromatin landscape of npT17 and pT17 cells both in vitro and in vivo. Compared to other CD4 T cell subsets, npT17 cells share accessible chromatin configurations with regulatory T cells, whereas pT17 cells exhibit features of both npT17 cells and type 1 helper T (T1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating T17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npT17 programs and restrains proinflammatory T1-like programs in T17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of T17 heterogeneity as potential targets to mitigate autoimmunity.