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Science 335 (6071): 984-989

Copyright © 2012 by the American Association for the Advancement of Science

The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses

Weldy V. Bonilla,1,2,* Anja Fröhlich,3,4,* Karin Senn,5,* Sandra Kallert,1,2 Marylise Fernandez,1,2 Susan Johnson,1,2 Mario Kreutzfeldt,1,6 Ahmed N. Hegazy,3,4,7 Christina Schrick,1,6 Padraic G. Fallon,8 Roman Klemenz,5 Susumu Nakae,9 Heiko Adler,10 Doron Merkler,1,6,11 Max Löhning,3,4,{dagger} Daniel D. Pinschewer1,2,{dagger}

Abstract: Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8+ T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

1 Department of Pathology and Immunology, University of Geneva, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
2 World Health Organization Collaborating Center for Vaccine Immunology, University of Geneva, Switzerland.
3 Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité–University Medicine Berlin, Berlin, Germany.
4 German Rheumatism Research Center (DRFZ), a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
5 Institute for Cancer Research, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
6 Division of Clinical Pathology, Geneva University Hospital, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
7 Department of Gastroenterology, Hepatology and Endocrinology, Campus Charité Mitte, Charité–University Medicine Berlin, Berlin, Germany.
8 Institute of Molecular Medicine, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.
9 The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, and Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), 4-1-8 Hncho, Kawaguchi, Saitama 332-0012, Japan.
10 Helmholtz Zentrum München, Institute of Molecular Immunology and Clinical Cooperation Group Hematopoietic Cell Transplantation (CCG HCT), Marchioninistraße 25, 81377 München, Germany.
11 Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.

{dagger} These authors contributed equally to this work. To whom correspondence should be addressed. E-mail: loehning{at}drfz.de (M.L.); daniel.pinschewer{at}gmx.ch (D.P.P.)

* These authors contributed equally to this work.


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