title: Programmed death-1 impairs secondary effector lung CD8⁺ T cells during respiratory virus reinfection.
abstract: Reinfections with respiratory viruses are common and cause significant clinical illness, yet precise mechanisms governing this susceptibility are ill defined. Lung Ag-specific CD8(+) T cells (T(CD8)) are impaired during acute viral lower respiratory infection by the inhibitory receptor programmed death-1 (PD-1). To determine whether PD-1 contributes to recurrent infection, we first established a model of reinfection by challenging B cell-deficient mice with human metapneumovirus (HMPV) several weeks after primary infection, and found that HMPV replicated to high titers in the lungs. A robust secondary effector lung TCD8 response was generated during reinfection, but these cells were more impaired and more highly expressed the inhibitory receptors PD-1, LAG-3, and 2B4 than primary T(CD8). In vitro blockade demonstrated that PD-1 was the dominant inhibitory receptor early after reinfection. In vivo therapeutic PD-1 blockade during HMPV reinfection restored lung T(CD8) effector functions (i.e., degranulation and cytokine production) and enhanced viral clearance. PD-1 also limited the protective efficacy of HMPV epitope-specific peptide vaccination and impaired lung T(CD8) during heterotypic influenza virus challenge infection. Our results indicate that PD-1 signaling may contribute to respiratory virus reinfection and evasion of vaccine-elicited immune responses. These results have important implications for the design of effective vaccines against respiratory viruses.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Erickson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Rogers
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Hastings
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Tollefson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232 john.williams@vanderbilt.edu.
authors.forename: John V
authors.identifier: http://orcid.org/0000-0001-8377-5175
authors.initials: JV
authors.lastname: Williams
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015550:Cell Degranulation / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D057131:Immune Evasion; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D018655:Lymphocyte Count; D029121:Metapneumovirus / Q000276:immunology; D051379:Mice; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018184:Paramyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D012141:Respiratory Tract Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family; D019562:Viral Load; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology; D014779:Virus Replication; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C490007:Cd244a protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D014765:Viral Vaccines; D000093322:Lymphocyte Activation Gene 3 Protein