The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8+ T cells in chronic viral infection

Anna-Friederike Marx; Sandra M Kallert; Tobias M Brunner; José A Villegas; Florian Geier; Jonas Fixemer; Tiago Abreu-Mota; Peter Reuther; Weldy V Bonilla; Jelizaveta Fadejeva; Mario Kreutzfeldt; Ingrid Wagner; Patricia Aparicio-Domingo; Leo Scarpellino; Mélanie Charmoy; Daniel T Utzschneider; Claudia Hagedorn; Min Lu; Karen Cornille; Karsten Stauffer; Florian Kreppel; Doron Merkler; Dietmar Zehn; Werner Held; Sanjiv A Luther; Max Löhning; Daniel D Pinschewer

doi:10.1016/j.immuni.2023.01.029

The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1⁺ CD8⁺ T cells in chronic viral infection

Immunity. 2023 Apr 11;56(4):813-828.e10. doi: 10.1016/j.immuni.2023.01.029. Epub 2023 Feb 20.

Authors

Anna-Friederike Marx¹, Sandra M Kallert², Tobias M Brunner³, José A Villegas⁴, Florian Geier⁵, Jonas Fixemer², Tiago Abreu-Mota², Peter Reuther², Weldy V Bonilla², Jelizaveta Fadejeva³, Mario Kreutzfeldt⁶, Ingrid Wagner⁶, Patricia Aparicio-Domingo⁴, Leo Scarpellino⁴, Mélanie Charmoy⁷, Daniel T Utzschneider⁸, Claudia Hagedorn⁹, Min Lu², Karen Cornille², Karsten Stauffer², Florian Kreppel⁹, Doron Merkler⁶, Dietmar Zehn¹⁰, Werner Held⁷, Sanjiv A Luther⁴, Max Löhning¹¹, Daniel D Pinschewer¹²

Affiliations

¹ Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. Electronic address: [email protected].
² Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland.
³ Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany.
⁴ Department of Immunobiology, University of Lausanne, 1066 Epalinges, Switzerland.
⁵ Department of Biomedicine, Bioinformatics Core Facility, University Hospital Basel, 4031 Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, Switzerland.
⁶ Department of Pathology and Immunology University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland.
⁷ Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
⁸ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
⁹ Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine, Stockumer Str. 10, 58453 Witten, Germany.
¹⁰ Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany.
¹¹ Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany. Electronic address: [email protected].
¹² Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. Electronic address: [email protected].

PMID: 36809763
DOI: 10.1016/j.immuni.2023.01.029

Abstract

T cell factor 1 (Tcf-1) expressing CD8⁺ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8⁺ T cells (CD8⁺SL) remain poorly defined. Studying CD8⁺ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8⁺SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8⁺ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8⁺SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8⁺SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8⁺SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8⁺SL-promoting pathway in the context of chronic viral infection.

Keywords: CD8(+)SL; IL-33; T cell factor 1; Tcf-1; chronic viral infection; interleukin-33; lymphocytic choriomeningitis virus; stem-like CD8(+) T cells; type I interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alarmins / metabolism
Animals
CD8-Positive T-Lymphocytes*
Interleukin-1 Receptor-Like 1 Protein / metabolism
Interleukin-33* / metabolism
Lymphocytic Choriomeningitis* / immunology
Lymphocytic choriomeningitis virus
Mice
Mice, Inbred C57BL
Persistent Infection
T Cell Transcription Factor 1 / metabolism

Substances

Alarmins
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
T Cell Transcription Factor 1