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T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus\u2013infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag\u2013induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.<\/jats:p>","DOI":"10.4049\/jimmunol.1403004","type":"journal-article","created":{"date-parts":[[2015,9,24]],"date-time":"2015-09-24T02:23:25Z","timestamp":1443061405000},"page":"4319-4330","source":"Crossref","is-referenced-by-count":38,"title":["Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion\u2013like Phenotype"],"prefix":"10.1093","volume":"195","author":[{"given":"John J","family":"Erickson","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K","family":"Hastings","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlo","family":"Gilchuk","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Joyce","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN 37232"},{"name":"Veterans Administration Tennessee Valley Healthcare System , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Shyr","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University School of Medicine , Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John V","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University School of Medicine , Nashville, TN 37232"},{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, Children\u2019s Hospital of Pittsburgh of University of Pittsburgh Medical Center , Pittsburgh, PA 15224"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,11,1]]},"reference":[{"key":"2025030704201495000_r1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nri3307","article-title":"Transcriptional control of effector and memory CD8+ T cell differentiation","volume":"12","author":"Kaech","year":"2012","journal-title":"Nat. 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