title: IL-33 Receptor-Expressing Regulatory T Cells Are Highly Activated, Th2 Biased and Suppress CD4 T Cell Proliferation through IL-10 and TGFβ Release.
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.
authors.affiliation: Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Siede
authors.affiliation: Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Fröhlich
authors.affiliation: Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Datsi
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.|The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
authors.forename: Domonkos V
authors.initials: DV
authors.lastname: Varga
authors.affiliation: Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Holecska
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D016130:Immunophenotyping; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33 / Q000235:genetics / Q000276:immunology*; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C556062:IL10 protein, mouse; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D016212:Transforming Growth Factor beta; D016753:Interleukin-10