Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22–producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ–producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ–expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22–expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22–inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.
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7 February 2022
Article|
January 13 2022
The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut
Ewelina Krzywinska
,
(Conceptualization, Formal analysis, Investigation, Visualization, Writing - original draft)
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Michal Sobecki
,
(Conceptualization, Formal analysis, Investigation, Visualization, Writing - original draft)
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Shunmugam Nagarajan
,
Shunmugam Nagarajan
(Methodology)
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Julian Zacharjasz
,
Julian Zacharjasz
(Investigation)
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Murtaza M. Tambuwala
,
Murtaza M. Tambuwala
(Formal analysis, Investigation, Methodology)
2
School of Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, UK
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Abigaelle Pelletier
,
Abigaelle Pelletier
(Investigation)
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
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Eoin Cummins
,
Eoin Cummins
(Formal analysis)
3
School of Medicine, University College Dublin, Conway Institute, Dublin, Ireland
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Dagmar Gotthardt
,
Dagmar Gotthardt
(Conceptualization)
4
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
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Joachim Fandrey
,
Joachim Fandrey
(Writing - review & editing)
5
Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
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Yann M. Kerdiles
,
Yann M. Kerdiles
(Conceptualization)
6
Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Institut National de la Santé et de la Recherche Médicale, U1104, Centre National de la Recherche Scientifique UMR7280, Marseille, France
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Carole Peyssonnaux
,
Carole Peyssonnaux
(Conceptualization, Writing - original draft)
7
Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Paris, France
8
Laboratory of Excellence GR-Ex, Paris, France
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Cormac T. Taylor
,
Cormac T. Taylor
(Formal analysis, Methodology)
3
School of Medicine, University College Dublin, Conway Institute, Dublin, Ireland
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Veronika Sexl
,
Veronika Sexl
(Conceptualization, Resources, Writing - review & editing)
4
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
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Christian Stockmann
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Correspondence to Christian Stockmann: christian.stockmann@anatomy.uzh.ch
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Ewelina Krzywinska
Conceptualization, Formal analysis, Investigation, Visualization, Writing - original draft
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Michal Sobecki
Conceptualization, Formal analysis, Investigation, Visualization, Writing - original draft
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Shunmugam Nagarajan
Methodology
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Julian Zacharjasz
Investigation
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Murtaza M. Tambuwala
Formal analysis, Investigation, Methodology
2
School of Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, UK
Abigaelle Pelletier
Investigation
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Eoin Cummins
Formal analysis
3
School of Medicine, University College Dublin, Conway Institute, Dublin, Ireland
Dagmar Gotthardt
Conceptualization
4
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
Joachim Fandrey
Writing - review & editing
5
Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
Yann M. Kerdiles
Conceptualization
6
Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Institut National de la Santé et de la Recherche Médicale, U1104, Centre National de la Recherche Scientifique UMR7280, Marseille, France
Carole Peyssonnaux
Conceptualization, Writing - original draft
7
Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Paris, France
8
Laboratory of Excellence GR-Ex, Paris, France
Cormac T. Taylor
Formal analysis, Methodology
3
School of Medicine, University College Dublin, Conway Institute, Dublin, Ireland
Veronika Sexl
Conceptualization, Resources, Writing - review & editing
4
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
Christian Stockmann
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Correspondence to Christian Stockmann: christian.stockmann@anatomy.uzh.ch
Disclosures: The authors declare no competing interests exist.
*
E. Krzywinska and M. Sobecki contributed equally to this paper.
Received:
April 28 2021
Revision Received:
November 03 2021
Accepted:
December 02 2021
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding
Funder(s):
Swiss National Fund
- Award Id(s): 310030_179235
Funder(s):
Swiss Cancer League
- Award Id(s): KFS-4398-02-2018,KFS-5402-08-2021
Funder(s):
University of Zurich
Funder(s):
Swiss National Centre for Competence in Research “Kidney.CH”
- Award Id(s): N-403-06-26 HCP
© 2022 Krzywinska et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2022) 219 (2): e20210909.
Article history
Received:
April 28 2021
Revision Received:
November 03 2021
Accepted:
December 02 2021
Citation
Ewelina Krzywinska, Michal Sobecki, Shunmugam Nagarajan, Julian Zacharjasz, Murtaza M. Tambuwala, Abigaelle Pelletier, Eoin Cummins, Dagmar Gotthardt, Joachim Fandrey, Yann M. Kerdiles, Carole Peyssonnaux, Cormac T. Taylor, Veronika Sexl, Christian Stockmann; The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut. J Exp Med 7 February 2022; 219 (2): e20210909. doi: https://doi.org/10.1084/jem.20210909
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