Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3
Roser Tachó-Piñot,
Christopher T. Stamper,
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
Affiliations
Roser Tachó-Piñot
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PL, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
Christopher T. Stamper
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Medical Unit for Lung and Allergy Diseases, Karolinska University Hospital, Stockholm, Sweden
James I. King
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PL, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
Veronika Matei-Rascu
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Erin Richardson
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Zhi Li
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Luke B. Roberts
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PL, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
John W. Bassett
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Medical Unit for Lung and Allergy Diseases, Karolinska University Hospital, Stockholm, Sweden
Felipe Melo-Gonzalez
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PL, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
Rémi Fiancette
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
I-Hsuan Lin
Bioinformatics Core Facility, University of Manchester, Manchester M13 9PL, UK
Alexander Dent
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
Yohsuke Harada
Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
Conor Finlay
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PL, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK; School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
Jenny Mjösberg
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Medical Unit for Lung and Allergy Diseases, Karolinska University Hospital, Stockholm, Sweden
David R. Withers
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Matthew R. Hepworth
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PL, UK; Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK; Corresponding author
Summary: 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.
