Marx, Kallert, and Brunner et al. studied chronic LCMV infection in mouse genetic/chimeric models selectively expressing the IL-33 receptor (ST2). ST2 signaling by IL-33, released from splenic T zone fibroblastic reticular cells early after infection, attenuated IFN-I responses and promoted Tcf-1 expression by, and expansion, differentiation and self-renewal of LCMV-specific stem-like (SL) CD8+ T cells to support TEFF cell formation and control infection. IL-33 increased chromatin accessibility of Tcf-1+ SL CD8+ T cells 4 days after LCMV infection in ST2-sufficient, but not -deficient T cells, imprinting an epigenetic profile distinct from that of TMEM and TEX cells.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. Electronic address: a.marx@unibas.ch. (2) Department of Biomedicine,
Author Info: (1) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. Electronic address: a.marx@unibas.ch. (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, Charit - Universittsmedizin Berlin, corporate member of Freie Universitt Berlin and Humboldt-Universitt 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 Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (7) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (8) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (9) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (10) Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charit - Universittsmedizin Berlin, corporate member of Freie Universitt Berlin and Humboldt-Universitt zu Berlin, 10117 Berlin, Germany; Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany. (11) Department of Pathology and Immunology University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. (12) Department of Pathology and Immunology University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. (13) Department of Immunobiology, University of Lausanne, 1066 Epalinges, Switzerland. (14) Department of Immunobiology, University of Lausanne, 1066 Epalinges, Switzerland. (15) Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland. (16) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia. (17) Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine, Stockumer Str. 10, 58453 Witten, Germany. (18) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (19) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (20) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. (21) Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine, Stockumer Str. 10, 58453 Witten, Germany. (22) Department of Pathology and Immunology University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. (23) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (24) Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland. (25) Department of Immunobiology, University of Lausanne, 1066 Epalinges, Switzerland. (26) Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charit - Universittsmedizin Berlin, corporate member of Freie Universitt Berlin and Humboldt-Universitt zu Berlin, 10117 Berlin, Germany; Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany. Electronic address: max.loehning@charite.de. (27) Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland. Electronic address: daniel.pinschewer@unibas.ch.
