title: IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection.
abstract: Exhaustion of CD8(+) T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain-dependent cytokines, on CD8(+) T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor β (IL2Rβ) chain is selectively maintained on CD8(+) T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8(+) T cells both in mice and humans. Genetic ablation of the IL2Rβ chain on CD8(+) T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1(hi) effectors; and rescues memory T-cell development and responsiveness to IL-7-dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8(+) T-cell exhaustion during chronic viral infection.
authors: Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors: Jean-Christophe
authors: JC
authors: Beltra
authors: Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5;
authors: Sara
authors: S
authors: Bourbonnais
authors: University of Montreal Hospital Research Center, Montreal, QC, Canada H2X 0A9;
authors: Nathalie
authors: N
authors: Bédard
authors: Immunovirology Laboratory, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, QC, Canada H7V 1B7;
authors: Tania
authors: T
authors: Charpentier
authors: Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors: Moana
authors: M
authors: Boulangé
authors: Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3C 3J7;
authors: Eva
authors: E
authors: Michaud
authors: Flow Cytometry Platform, Sainte-Justine University Hospital Research Center, QC, Canada H3T 1C5;
authors: Ines
authors: I
authors: Boufaied
authors: University of Montreal Hospital Research Center, Montreal, QC, Canada H2X 0A9; Department of Family Medicine and Emergency Medicine, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H2X 0A9;
authors: Julie
authors: J
authors: Bruneau
authors: University of Montreal Hospital Research Center, Montreal, QC, Canada H2X 0A9; Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3T 1J4;
authors: Naglaa H
authors: NH
authors: Shoukry
authors: Immunovirology Laboratory, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, QC, Canada H7V 1B7;
authors: Alain
authors: 0000-0002-7913-871X
authors: A
authors: Lamarre
authors: Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3C 3J7; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3T 1C5 helene.decaluwe@umontreal.ca.
authors: Hélène
authors: H
authors: Decaluwe
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016174:Hepacivirus / Q000276:immunology / Q000472:pathogenicity; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics* / Q000276:immunology; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics / Q000378:metabolism
chemical_list: C490007:Cd244a protein, mouse; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7; D000071176:Signaling Lymphocytic Activation Molecule Family
keywords: CD8 T cell; IL-15; IL-2; exhaustion; memory T cell