title: Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype.
abstract: Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. 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-infected 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-induced 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.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: John J
authors.initials: JJ
authors.lastname: Erickson
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Sherry
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Hastings
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Pavlo
authors.initials: P
authors.lastname: Gilchuk
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; Veterans Administration Tennessee Valley Healthcare System, Nashville, TN 37232;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224 jvw@chp.edu.
authors.forename: John V
authors.initials: JV
authors.lastname: Williams
mesh_terms: D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016000:Cluster Analysis; D020869:Gene Expression Profiling / Q000379:methods; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D029121:Metapneumovirus / Q000276:immunology* / Q000502:physiology; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018184:Paramyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology; D059467:Transcriptome / Q000235:genetics / Q000276:immunology
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor