BACH2 regulates diversification of regulatory and proinflammatory chromatin states in T H 17 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.