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

doi:10.1016/j.celrep.2023.113425

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 journal › Article › peer-review

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 language	English
Article number	113425
Number of pages	22
Journal	Cell Reports
Volume	42
Issue number	11
Early online date	10 Nov 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.113425
Publication status	Published - 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

Access to Document

10.1016/j.celrep.2023.113425Licence: Creative Commons: Attribution (CC BY)

TachóPiñotR2023Bcl6Final published version, 4.69 MBLicence: Creative Commons: Attribution (CC BY)

Revealing anti-tumour T cell recruitment and recirculation in vivo to optimise therapeutic intervention.
Withers, D.
Cancer Research Uk
1/02/19 → 31/01/22
Project: Research
ILC3 control of adaptive immune responses
Withers, D.
THE WELLCOME TRUST
1/04/16 → 30/09/21
Project: Research

Cite this

Tachó-Piñot, R., Stamper, C. T., King, J. A., Matei-Rascu, V., Richardson, E., Li, Z., Roberts, L. B., Bassett, J. W., Melo-Gonzalez, F., Fiancette, R., Lin, I.-H., Dent, A., Harada, Y., Finlay, C., Mjösberg, J., Withers, D. R., & Hepworth, M. R. (2023). Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3. Cell Reports, 42(11), Article 113425. https://doi.org/10.1016/j.celrep.2023.113425

@article{0846e30cbabc4327885f3853dd9651ed,

title = "Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3",

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.",

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",

author = "Roser Tach{\'o}-Pi{\~n}ot and Stamper, {Christopher T.} and King, {James A.} and Veronika Matei-Rascu and Erin Richardson and Zhi Li and Roberts, {Luke B.} and Bassett, {John W.} and Felipe Melo-Gonzalez and R{\'e}mi Fiancette and I-Hsuan Lin and Alexander Dent and Yohsuke Harada and Conor Finlay and Jenny Mj{\"o}sberg and Withers, {David R.} and Hepworth, {Matthew R.}",

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 Mj{\"o}sberg 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{\textquoteright}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: {\textcopyright} 2023 The Author(s). Published by Elsevier Inc.",

year = "2023",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2023.113425",

language = "English",

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Tachó-Piñot, R, Stamper, CT, King, JA, Matei-Rascu, V, Richardson, E, Li, Z, Roberts, LB, Bassett, JW, Melo-Gonzalez, F, Fiancette, R, Lin, I-H, Dent, A, Harada, Y, Finlay, C, Mjösberg, J, Withers, DR & Hepworth, MR 2023, 'Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3', Cell Reports, vol. 42, no. 11, 113425. https://doi.org/10.1016/j.celrep.2023.113425

TY - JOUR

T1 - Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3

AU - Tachó-Piñot, Roser

AU - Stamper, Christopher T.

AU - King, James A.

AU - Matei-Rascu, Veronika

AU - Richardson, Erin

AU - Li, Zhi

AU - Roberts, Luke B.

AU - Bassett, John W.

AU - Melo-Gonzalez, Felipe

AU - Fiancette, Rémi

AU - Lin, I-Hsuan

AU - Dent, Alexander

AU - Harada, Yohsuke

AU - Finlay, Conor

AU - Mjösberg, Jenny

AU - Withers, David R.

AU - Hepworth, Matthew R.

N1 - 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.

PY - 2023/11/28

Y1 - 2023/11/28

N2 - 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.

AB - 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.

KW - Animals

KW - Humans

KW - Mice

KW - Immunity, Innate

KW - Lymphocytes/metabolism

KW - Lymphoid Tissue/metabolism

KW - Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism

KW - Proto-Oncogene Proteins c-bcl-6/metabolism

KW - Transcription Factors/metabolism

U2 - 10.1016/j.celrep.2023.113425

DO - 10.1016/j.celrep.2023.113425

M3 - Article

C2 - 37950867

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113425

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

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Projects

Revealing anti-tumour T cell recruitment and recirculation in vivo to optimise therapeutic intervention.

ILC3 control of adaptive immune responses

Cite this