Programmed death-1 impairs secondary effector lung CD8⁺ T cells during respiratory virus reinfection

J Immunol. 2014 Nov 15;193(10):5108-17. doi: 10.4049/jimmunol.1302208. Epub 2014 Oct 22.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Degranulation / immunology
  • Gene Expression Regulation
  • Humans
  • Immune Evasion
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocyte Count
  • Metapneumovirus / immunology
  • Mice
  • Orthomyxoviridae / immunology
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Paramyxoviridae Infections / genetics
  • Paramyxoviridae Infections / immunology*
  • Paramyxoviridae Infections / prevention & control
  • Paramyxoviridae Infections / virology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Respiratory Tract Infections / genetics
  • Respiratory Tract Infections / immunology*
  • Respiratory Tract Infections / pathology
  • Respiratory Tract Infections / virology
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Family
  • Viral Load
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / immunology
  • Virus Replication

Substances

  • Antigens, CD
  • Cd244a protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • Signaling Lymphocytic Activation Molecule Family
  • Viral Vaccines
  • Lymphocyte Activation Gene 3 Protein