Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 37, Pages E5444-E5453Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1604256113
Keywords
CD8 T cell; IL-2; IL-15; exhaustion; memory T cell
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP-130469]
- Fonds de Recherche du Quebec-Sante (FRQS)
- Leukemia and Lymphoma Society of Canada
- Cole Foundation
- FRQS
- Canadian Child Health Clinician Scientist Program
- CHIR [MOP-89797, MOP-133680]
- FRQS AIDS and Infectious Diseases Network
- FRQS Chercheurs Boursier-Senior Award
- University of Montreal
- Sainte-Justine University Hospital Research Center Foundation
- American Association of Immunologists
- J.-Louis Levesque Foundation
- Alberta Innovates [201201140] Funding Source: researchfish
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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 beta (IL2R beta) 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 IL2R beta 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.
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