IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection

Jean-Christophe Beltra; Sara Bourbonnais; Nathalie Bédard; Tania Charpentier; Moana Boulangé; Eva Michaud; Ines Boufaied; Julie Bruneau; Naglaa H Shoukry; Alain Lamarre; Hélène Decaluwe

doi:10.1073/pnas.1604256113

IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection

Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5444-53. doi: 10.1073/pnas.1604256113. Epub 2016 Aug 29.

Authors

Affiliations

¹ 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;
² Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5;
³ University of Montreal Hospital Research Center, Montreal, QC, Canada H2X 0A9;
⁴ Immunovirology Laboratory, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, QC, Canada H7V 1B7;
⁵ Flow Cytometry Platform, Sainte-Justine University Hospital Research Center, QC, Canada H3T 1C5;
⁶ 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;
⁷ 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;
⁸ 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.

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.

Keywords: CD8 T cell; IL-15; IL-2; exhaustion; memory T cell.

Publication types

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

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / pathology
Hepacivirus / immunology
Hepacivirus / pathogenicity
Hepatitis A Virus Cellular Receptor 2 / genetics
Hepatitis A Virus Cellular Receptor 2 / metabolism
Humans
Immunologic Memory
Interleukin-15 / genetics*
Interleukin-15 / metabolism
Interleukin-2 / genetics*
Interleukin-2 / metabolism
Interleukin-2 Receptor beta Subunit / genetics*
Interleukin-2 Receptor beta Subunit / immunology
Interleukin-7 / genetics
Interleukin-7 / immunology
Lymphocytic Choriomeningitis / genetics
Lymphocytic Choriomeningitis / immunology*
Lymphocytic Choriomeningitis / pathology
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology
Lymphocytic choriomeningitis virus / pathogenicity
Mice
Signaling Lymphocytic Activation Molecule Family / genetics
Signaling Lymphocytic Activation Molecule Family / metabolism

Substances

Cd244a protein, mouse
Havcr2 protein, mouse
Hepatitis A Virus Cellular Receptor 2
Il2rb protein, mouse
Interleukin-15
Interleukin-2
Interleukin-2 Receptor beta Subunit
Interleukin-7
Signaling Lymphocytic Activation Molecule Family