title: High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival.
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.
authors.affiliation: Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Daniel T
authors.identifier: 0000-0003-2205-9057
authors.initials: DT
authors.lastname: Utzschneider
authors.affiliation: Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Alfei
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roelli
authors.affiliation: Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: David
authors.identifier: 0000-0001-8985-4704
authors.initials: D
authors.lastname: Barras
authors.affiliation: 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.
authors.forename: Vijaykumar
authors.identifier: 0000-0003-0014-3274
authors.initials: V
authors.lastname: Chennupati
authors.affiliation: 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.
authors.forename: Stephanie
authors.identifier: 0000-0002-0817-0472
authors.initials: S
authors.lastname: Darbre
authors.affiliation: 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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Division of Experimental Virology, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.affiliation: 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.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zehn
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000956:Antigens, Viral / Q000097:blood*; D002454:Cell Differentiation; D002470:Cell Survival; D002908:Chronic Disease; D053699:Interleukin-7 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; D053699:Interleukin-7 Receptor alpha Subunit; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D000093322:Lymphocyte Activation Gene 3 Protein