Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity

Rémi Fiancette; Conor M. Finlay; Claire Willis; Sarah L. Bevington; Jake Soley; Sky T. H. Ng; Syed Murtuza Baker; Simon Andrews; Matthew R. Hepworth; David R. Withers

doi:10.1038/s41590-021-01024-x

Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity

Rémi Fiancette, Conor M. Finlay, Claire Willis, Sarah L. Bevington, Jake Soley, Sky T. H. Ng, Syed Murtuza Baker, Simon Andrews, Matthew R. Hepworth^*, David R. Withers^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)⁺ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR⁺ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

Original language	English
Pages (from-to)	1245–1255
Number of pages	11
Journal	Nature Immunology
Volume	22
Early online date	23 Sept 2021
DOIs	https://doi.org/10.1038/s41590-021-01024-x
Publication status	Published - Oct 2021

Bibliographical note

Acknowledgements:
We thank A. Ptasinska (Institute of Cancer and Genomic Sciences, University of Birmingham), for advice and help with ATAC–seq experiments, Genomics Birmingham, the genomic and sequencing facility of the University of Birmingham, and the University of Birmingham Flow Cytometry Platform. We thank G. Howell and the University of Manchester flow cytometry core, and A. Hayes and C. Morrisroe in the University of Manchester Genomic Technologies core facility for their help with scRNA-seq. We thank G. Frankel (Imperial College, London), for the provision of C. rodentium ICC169. We thank the following for their kind provision of mice: D. Littman (Howard Hughes Medical Institute, New York; Rorccre mice), A. McKenzie (MRC-LMB, Cambridge; Rorafl/fl mice), B. Stockinger (The Francis Crick Institute, London; Il17acre mice), S. Reiner (Columbia University, New York; Tbx21fl/fl mice) and J. Fehling (Ulm University, Germany; Rosa26tdRFP mice). We thank C. Stehle and C. Romagnani (Charité University Medicine Berlin, Germany) for critical discussion of data and the manuscript. This work was supported by a Senior Research Fellowship from the Wellcome Trust to D.R.W. (110199/Z/15/Z) and by a Royal Society and Wellcome Trust Sir Henry Dale Fellowship (105644/Z/14/Z) and a Lister Institute of Preventative Medicine Prize to M.R.H. This work was also supported by a Wellcome Trust ISSF funding award (105610/Z/14/Z) to M.R.H. C.M.F. was supported by a Wellcome Investigator award (106898/A/15/Z) to J. E. Allen.

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10.1038/s41590-021-01024-x

https://research.manchester.ac.uk/en/publications/reciprocal-transcription-factor-networks-govern-tissue-resident-i

ILC3 control of adaptive immune responses
Withers, D.
THE WELLCOME TRUST
1/04/16 → 30/09/21
Project: Research

Cite this

@article{ac7d1cc7a76749599d0f3f3852a1d372,

title = "Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity",

abstract = "Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.",

author = "R{\'e}mi Fiancette and Finlay, {Conor M.} and Claire Willis and Bevington, {Sarah L.} and Jake Soley and Ng, {Sky T. H.} and {Murtuza Baker}, Syed and Simon Andrews and Hepworth, {Matthew R.} and Withers, {David R.}",

note = "Acknowledgements: We thank A. Ptasinska (Institute of Cancer and Genomic Sciences, University of Birmingham), for advice and help with ATAC–seq experiments, Genomics Birmingham, the genomic and sequencing facility of the University of Birmingham, and the University of Birmingham Flow Cytometry Platform. We thank G. Howell and the University of Manchester flow cytometry core, and A. Hayes and C. Morrisroe in the University of Manchester Genomic Technologies core facility for their help with scRNA-seq. We thank G. Frankel (Imperial College, London), for the provision of C. rodentium ICC169. We thank the following for their kind provision of mice: D. Littman (Howard Hughes Medical Institute, New York; Rorccre mice), A. McKenzie (MRC-LMB, Cambridge; Rorafl/fl mice), B. Stockinger (The Francis Crick Institute, London; Il17acre mice), S. Reiner (Columbia University, New York; Tbx21fl/fl mice) and J. Fehling (Ulm University, Germany; Rosa26tdRFP mice). We thank C. Stehle and C. Romagnani (Charit{\'e} University Medicine Berlin, Germany) for critical discussion of data and the manuscript. This work was supported by a Senior Research Fellowship from the Wellcome Trust to D.R.W. (110199/Z/15/Z) and by a Royal Society and Wellcome Trust Sir Henry Dale Fellowship (105644/Z/14/Z) and a Lister Institute of Preventative Medicine Prize to M.R.H. This work was also supported by a Wellcome Trust ISSF funding award (105610/Z/14/Z) to M.R.H. C.M.F. was supported by a Wellcome Investigator award (106898/A/15/Z) to J. E. Allen.",

year = "2021",

month = oct,

doi = "10.1038/s41590-021-01024-x",

language = "English",

volume = "22",

pages = "1245–1255",

journal = "Nature Immunology",

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T1 - Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity

AU - Fiancette, Rémi

AU - Finlay, Conor M.

AU - Willis, Claire

AU - Bevington, Sarah L.

AU - Soley, Jake

AU - Ng, Sky T. H.

AU - Murtuza Baker, Syed

AU - Andrews, Simon

AU - Hepworth, Matthew R.

AU - Withers, David R.

N1 - Acknowledgements: We thank A. Ptasinska (Institute of Cancer and Genomic Sciences, University of Birmingham), for advice and help with ATAC–seq experiments, Genomics Birmingham, the genomic and sequencing facility of the University of Birmingham, and the University of Birmingham Flow Cytometry Platform. We thank G. Howell and the University of Manchester flow cytometry core, and A. Hayes and C. Morrisroe in the University of Manchester Genomic Technologies core facility for their help with scRNA-seq. We thank G. Frankel (Imperial College, London), for the provision of C. rodentium ICC169. We thank the following for their kind provision of mice: D. Littman (Howard Hughes Medical Institute, New York; Rorccre mice), A. McKenzie (MRC-LMB, Cambridge; Rorafl/fl mice), B. Stockinger (The Francis Crick Institute, London; Il17acre mice), S. Reiner (Columbia University, New York; Tbx21fl/fl mice) and J. Fehling (Ulm University, Germany; Rosa26tdRFP mice). We thank C. Stehle and C. Romagnani (Charité University Medicine Berlin, Germany) for critical discussion of data and the manuscript. This work was supported by a Senior Research Fellowship from the Wellcome Trust to D.R.W. (110199/Z/15/Z) and by a Royal Society and Wellcome Trust Sir Henry Dale Fellowship (105644/Z/14/Z) and a Lister Institute of Preventative Medicine Prize to M.R.H. This work was also supported by a Wellcome Trust ISSF funding award (105610/Z/14/Z) to M.R.H. C.M.F. was supported by a Wellcome Investigator award (106898/A/15/Z) to J. E. Allen.

PY - 2021/10

Y1 - 2021/10

N2 - Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

AB - Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

U2 - 10.1038/s41590-021-01024-x

DO - 10.1038/s41590-021-01024-x

M3 - Article

SN - 1529-2908

VL - 22

SP - 1245

EP - 1255

JO - Nature Immunology

JF - Nature Immunology

ER -

Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity

Abstract

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ILC3 control of adaptive immune responses

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