Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3

• DOI: 10.1016/j.celrep.2023.113425
• Publication Date: 2023-11-10T19:20:08Z
• Authors: Roser Tachó-Piñot; Christopher T. St...; James I. King; Veronika Matei-Rascu; Erin Richardson; Zhi Li; Luke B. Roberts; John W. Bassett; Felipe Melo-Gonzalez; Rémi Fiancette; I-Hsuan Lin; Alexander Dent; Yohsuke Harada; Conor Finlay; Jenny Mjösberg; David R. Withers; Matthew R. Hepworth
• Keywords: Lymphoid tissue inducer; QH301-705.5; Lymphoid Tissue; Bcl6; Immunology; innate lymphoid cells; ILC3; Innate lymphoid cells; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism; intestinal immunity; Article; Mice; microbiota; Lymphoid Tissue/metabolism; Animals; Humans; Transcription Factors/metabolism; Lymphocytes; Biology (General); transcription factor; lymphoid tissue inducer; Microbiota; CP: Immunology; Nuclear Receptor Subfamily 1, Group F, Member 3; Lymphocytes/metabolism; Immunity, Innate; IL-17; Proto-Oncogene Proteins c-bcl-6; Intestinal immunity; Transcription factor; Proto-Oncogene Proteins c-bcl-6/metabolism; Transcription Factors

Innate lymphoid cells (ILCs) are tissue-resident effector cells with roles in tissue homeostasis, protective immunity, and inflammatory disease. Group 3 ILCs (ILC3s) are classically defined by the master transcription factor RORγt. However, ILC3 can be further subdivided into subsets that share type 3 effector modules that exhibit significant ontological, transcriptional, phenotypic, and functional heterogeneity. Notably lymphoid tissue inducer (LTi)-like ILC3s mediate effector functions not typically associated with other RORγt-expressing lymphocytes, suggesting that additional transcription factors contribute to dictate ILC3 subset phenotypes. Here, we identify Bcl6 as a subset-defining transcription factor of LTi-like ILC3s in mice and humans. Deletion of Bcl6 results in dysregulation of the LTi-like ILC3 transcriptional program and markedly enhances expression of interleukin-17A (IL-17A) and IL-17F in LTi-like ILC3s in a manner in part dependent upon the commensal microbiota-and associated with worsened inflammation in a model of colitis. Together, these findings redefine our understanding of ILC3 subset biology.