IL-33 Receptor-Expressing Regulatory T Cells Are Highly Activated, Th2 Biased and Suppress CD4 T Cell Proliferation through IL-10 and TGFβ Release

PLoS One. 2016 Aug 22;11(8):e0161507. doi: 10.1371/journal.pone.0161507. eCollection 2016.

Authors

Julia Siede^{1

2}, Anja Fröhlich^{1

2}, Angeliki Datsi^{1

2}, Ahmed N Hegazy^{3

4}, Domonkos V Varga^{1

2}, Vivien Holecska^{1

2}, Hirohisa Saito⁵, Susumu Nakae^{6

7}, Max Löhning^{1

2}

Affiliations

¹ Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
³ Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
⁴ The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford, United Kingdom.
⁵ Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
⁶ Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁷ Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan.

Abstract

Immunomodulatory Foxp3+ regulatory T cells (Tregs) form a heterogeneous population consisting of subsets with different activation states, migratory properties and suppressive functions. Recently, expression of the IL-33 receptor ST2 was shown on Tregs in inflammatory settings. Here we report that ST2 expression identifies highly activated Tregs in mice even under homeostatic conditions. ST2+ Tregs preferentially accumulate at non-lymphoid sites, likely mediated by their high expression of several chemokine receptors facilitating tissue homing. ST2+ Tregs exhibit a Th2-biased character, expressing GATA-3 and producing the Th2 cytokines IL-5 and IL-13 -especially in response to IL-33. Yet, IL-33 is dispensable for the generation and maintenance of these cells in vivo. Furthermore, ST2+ Tregs are superior to ST2- Tregs in suppressing CD4+ T cell proliferation in vitro independent of IL-33. This higher suppressive capacity is partially mediated by enhanced production and activation of the anti-inflammatory cytokines IL-10 and TGFβ. Thus, ST2 expression identifies a highly activated, strongly suppressive Treg subset preferentially located in non-lymphoid tissues. Here ST2+ Tregs may be well positioned to immediately react to IL-33 alarm signals. Their specific properties may render ST2+ Tregs useful targets for immunomodulatory therapies.

MeSH terms

Animals
Cell Lineage / immunology
Cell Proliferation
GATA3 Transcription Factor / genetics
GATA3 Transcription Factor / immunology
Gene Expression Regulation
Immunophenotyping
Interleukin-1 Receptor-Like 1 Protein / deficiency
Interleukin-1 Receptor-Like 1 Protein / genetics
Interleukin-1 Receptor-Like 1 Protein / immunology*
Interleukin-10 / genetics
Interleukin-10 / immunology*
Interleukin-13 / genetics
Interleukin-13 / immunology
Interleukin-33 / genetics
Interleukin-33 / immunology*
Interleukin-5 / genetics
Interleukin-5 / immunology
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Signal Transduction
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / immunology*

Substances

GATA3 Transcription Factor
Gata3 protein, mouse
IL10 protein, mouse
Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-13
Interleukin-33
Interleukin-5
Transforming Growth Factor beta
Interleukin-10

Grants and funding

This work was supported by the German Research Foundation (www.dfg.de) (SFB650, grant TP28; GRK1121, grant TPB1; and grant LO1542/3-1), the German Federal Ministry of Education and Research (www.bmbf.de) (e:Bio/T-Sys, grant 0316164G), the Swiss National Science Foundation (http://www.snf.ch) (Sinergia, grant CRSII3_160772/1), Volkswagen Foundation (www.volkswagenstiftung.de) (Lichtenberg Program) (to M.L.) and Willy Robert Pitzer Foundation (www.wrp-stiftung.de) (Osteoarthritis Research Program) (to M.L.), in part by the International Max Planck Research School for Infectious Diseases and Immunology (https://www.zibi-graduateschool-berlin.de) (to J.S., A.D. and D.V.V.), a European Molecular Biology Organization (EMBO) (http://www.embo.org) long-term fellowship (ALTF 116-2012 and ALTF 314-2012) (to A.N.H.) and a Marie Skłodowska-Curie Research Fellow (http://ec.europa.eu/research/mariecurieactions) (proposal 330621) (to A.N.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.