title: T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses.
abstract: During infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4(+) T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell-intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4(+) T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Rheumatism Research Center Berlin, 10117 Berlin, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland; and.
authors.forename: Weldy V
authors.initials: WV
authors.lastname: Bonilla
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Rheumatism Research Center Berlin, 10117 Berlin, Germany;
authors.forename: Anja
authors.initials: A
authors.lastname: Fröhlich
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Rheumatism Research Center Berlin, 10117 Berlin, Germany;
authors.forename: Caroline
authors.initials: C
authors.lastname: Helmstetter
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Rheumatism Research Center Berlin, 10117 Berlin, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Peine
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland; and daniel.pinschewer@gmx.ch loehning@drfz.de.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Rheumatism Research Center Berlin, 10117 Berlin, Germany; daniel.pinschewer@gmx.ch loehning@drfz.de.
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D002469:Cell Separation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology*; D019041:L-Selectin / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D019041:L-Selectin; D007371:Interferon-gamma
keywords: CD4 T cell; IL-33; ST2; Th1 cell; virus infection
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