ST2, the receptor for the alarmin IL-33, is expressed by a subset of regulatory T (T reg) cells residing in nonlymphoid tissues, and these cells can potently expand upon provision of exogenous IL-33. Whether the accumulation and residence of T reg cells in tissues requires their cell-intrinsic expression of and signaling by ST2, or whether indirect IL-33 signaling acting on other cells suffices, has been a matter of contention. Here, we report that ST2 expression on T reg cells is largely dispensable for their accumulation and residence in nonlymphoid organs, including the visceral adipose tissue (VAT), even though cell-intrinsic sensing of IL-33 promotes type 2 cytokine production by VAT-residing T reg cells. In addition, we uncovered a novel ST2-dependent role for T reg cells in limiting the size of IL-17A–producing γδT cells in the CNS in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Finally, ST2 deficiency limited to T reg cells led to disease exacerbation in EAE.
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1 February 2021
Brief Definitive Report|
October 23 2020
T reg cell–intrinsic requirements for ST2 signaling in health and neuroinflammation
Saskia Hemmers
,
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, New York, NY
2
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY
Correspondence to Saskia Hemmers: hemmerss@mskcc.org
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Michail Schizas
,
Michail Schizas
Formal analysis, Software, Visualization
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, New York, NY
2
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY
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Alexander Y. Rudensky
Conceptualization, Data curation, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, New York, NY
2
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY
Alexander Y. Rudensky: rudenska@mskcc.org
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Saskia Hemmers
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, New York, NY
2
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY
Michail Schizas
Formal analysis, Software, Visualization
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, New York, NY
2
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY
Alexander Y. Rudensky
Conceptualization, Data curation, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, New York, NY
2
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY
Disclosures: A.Y. Rudensky reported personal fees from Sonoma Biotherapeutics outside the submitted work. No other disclosures were reported.
Alexander Y. Rudensky: rudenska@mskcc.org
Correspondence to Saskia Hemmers: hemmerss@mskcc.org
Received:
June 15 2020
Revision Received:
August 11 2020
Accepted:
September 16 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Memorial Sloan-Kettering Cancer Center
(NO AWARD)
National Cancer Institute
(P30 CA008748)
National Institutes of Health
(AI034206)
© 2020 Hemmers et al.
2020
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 (2021) 218 (2): e20201234.
Article history
Received:
June 15 2020
Revision Received:
August 11 2020
Accepted:
September 16 2020
Citation
Saskia Hemmers, Michail Schizas, Alexander Y. Rudensky; T reg cell–intrinsic requirements for ST2 signaling in health and neuroinflammation. J Exp Med 1 February 2021; 218 (2): e20201234. doi: https://doi.org/10.1084/jem.20201234
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