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.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)