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J Exp Med. 2016 Aug 22;213(9):1819-34. doi: 10.1084/jem.20150598. Epub 2016 Jul 25.

High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival.

Author information

1
Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
2
Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
3
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
4
Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland Ludwig Center for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland.
5
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland World Health Organization Collaborating Center for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.
6
Ludwig Center for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland Faculty of Biology and Medicine, Department of Oncology, University of Lausanne, 1015 Lausanne, Switzerland Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
7
Division of Experimental Virology, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland.
8
Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland dietmar.zehn@tum.de.

Abstract

Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.

PMID:
27455951
PMCID:
PMC4995073
DOI:
10.1084/jem.20150598
[Indexed for MEDLINE]
Free PMC Article

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