Pratiksha I. Thakore, Alexandra Schnell, Linglin Huang, Maryann Zhao, Yu Hou, Elena Christian, Sarah Zaghouani, Chao Wang, Vasundhara Singh, Anvita Singaraju, Rajesh Kumar Krishnan, Deneen Kozoriz, Sai Ma, Venkat Sankar, Samuele Notarbartolo, Jason D. Buenrostro, Federica Sallusto, Nikolaos A. Patsopoulos, Orit Rozenblatt-Rosen, Vijay K. Kuchroo, Aviv Regev
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引用次数: 0
Abstract
Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) 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 TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity. Regulating the balance between TH17 cells that drive autoimmune inflammation and nonpathogenic TH17 cells is critical for limiting autoimmune pathology. Here, the authors extensively characterize these two cell states at the transcriptomic and epigenetic levels and show how BACH2 is protective in this context.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.