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

Roser Tachó-Piñot, Christopher T. Stamper, James A. 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number113425
Number of pages22
JournalCell Reports
Volume42
Issue number11
Early online date10 Nov 2023
DOIs
Publication statusPublished - 28 Nov 2023

Bibliographical note

Acknowledgments:
The authors acknowledge members of the Hepworth lab for critical discussion. We thank Gareth Howell, David Chapman, and the University of Manchester flow cytometry; Andy Hayes, Claire Morrisroe, and the Manchester Genomic Technologies Core Facility core; and Melissa Lawson and the University of Manchester Gnotbiotic Facility for support. We also thank Pedro Papotto and Joanne Konkel (University of Manchester) and Michelle Linterman (Babraham Institute) for providing experimental animals and technical support. R.T.-P. was supported by funding from the Medical Research Council (MRC) Doctroal Training Programme. Research in the Withers lab was supported by a Senior Research Fellowship to D.R.W. from the Wellcome Trust (grant number 110199/Z/15/Z) and a Cancer Research UK Immunology Project Award (C54019/A27535). Research in the Mjösberg lab is supported by the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, and the Swedish Research Council, and we thank the SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. Funding was received from the Swedish Research Council, The Swedish Cancer Foundation, The Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 850963). Research in the Hepworth Laboratory is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 105644/Z/14/Z), a BBSRC responsive mode grant (BB/T014482/1), and a Lister Institute of Preventative Medicine Prize.

Copyright:
© 2023 The Author(s). Published by Elsevier Inc.

Keywords

  • Animals
  • Humans
  • Mice
  • Immunity, Innate
  • Lymphocytes/metabolism
  • Lymphoid Tissue/metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
  • Proto-Oncogene Proteins c-bcl-6/metabolism
  • Transcription Factors/metabolism

Fingerprint

Dive into the research topics of 'Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3'. Together they form a unique fingerprint.

Cite this