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.
Copyright © 2014 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Cell Degranulation / immunology
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Gene Expression Regulation
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Humans
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Immune Evasion
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Lung / immunology
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Lung / pathology
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Lung / virology
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Lymphocyte Activation Gene 3 Protein
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Lymphocyte Count
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Metapneumovirus / immunology
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Mice
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Orthomyxoviridae / immunology
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Orthomyxoviridae Infections / genetics
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Orthomyxoviridae Infections / immunology*
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Orthomyxoviridae Infections / pathology
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Orthomyxoviridae Infections / virology
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Paramyxoviridae Infections / genetics
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Paramyxoviridae Infections / immunology*
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Paramyxoviridae Infections / prevention & control
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Paramyxoviridae Infections / virology
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology*
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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Respiratory Tract Infections / genetics
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Respiratory Tract Infections / immunology*
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Respiratory Tract Infections / pathology
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Respiratory Tract Infections / virology
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Signal Transduction
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Signaling Lymphocytic Activation Molecule Family
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Viral Load
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Viral Vaccines / administration & dosage
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Viral Vaccines / immunology
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Virus Replication
Substances
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Antigens, CD
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Cd244a protein, mouse
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic
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Signaling Lymphocytic Activation Molecule Family
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Viral Vaccines
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Lymphocyte Activation Gene 3 Protein