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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.<\/jats:p>","DOI":"10.1084\/jem.20150598","type":"journal-article","created":{"date-parts":[[2016,7,25]],"date-time":"2016-07-25T10:12:22Z","timestamp":1469441542000},"page":"1819-1834","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":176,"title":["High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2205-9057","authenticated-orcid":false,"given":"Daniel T.","family":"Utzschneider","sequence":"first","affiliation":[{"name":"Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland 1"},{"name":"Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Alfei","sequence":"additional","affiliation":[{"name":"Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland 1"},{"name":"Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Roelli","sequence":"additional","affiliation":[{"name":"Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland 1"},{"name":"Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland 2"},{"name":"Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8985-4704","authenticated-orcid":false,"given":"David","family":"Barras","sequence":"additional","affiliation":[{"name":"Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-3274","authenticated-orcid":false,"given":"Vijaykumar","family":"Chennupati","sequence":"additional","affiliation":[{"name":"Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland 1"},{"name":"Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland 2"},{"name":"Ludwig Center for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0817-0472","authenticated-orcid":false,"given":"Stephanie","family":"Darbre","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland 4"},{"name":"World Health Organization Collaborating Center for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Delorenzi","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland 6"},{"name":"Faculty of Biology and Medicine, Department of Oncology, University of Lausanne, 1015 Lausanne, Switzerland 7"},{"name":"Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel D.","family":"Pinschewer","sequence":"additional","affiliation":[{"name":"Division of Experimental Virology, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Zehn","sequence":"additional","affiliation":[{"name":"Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland 1"},{"name":"Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,7,25]]},"reference":[{"key":"2023072603440504800_bib1","doi-asserted-by":"publisher","first-page":"S6","DOI":"10.1016\/j.jhep.2005.11.004","article-title":"Epidemiology of viral hepatitis and HIV co-infection","volume":"44","author":"Alter","year":"2006","journal-title":"J. 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