BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells

Interleukin-17 (IL-17)-producing helper T (T(H)17) cells are heterogenous and consist of nonpathogenic T(H)17 (npT(H)17) cells that contribute to tissue homeostasis and pathogenic T(H)17 (pT(H)17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T(H)17 heterogeneity and discover substantial differences in the chromatin landscape of npT(H)17 and pT(H)17 cells both in vitro and in vivo. Compared to other CD4(+) T cell subsets, npT(H)17 cells share accessible chromatin configurations with regulatory T cells, whereas pT(H)17 cells exhibit features of both npT(H)17 cells and type 1 helper T (T(H)1) 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 T(H)17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npT(H)17 programs and restrains proinflammatory T(H)1-like programs in T(H)17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of T(H)17 heterogeneity as potential targets to mitigate autoimmunity.