Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection

J Immunol. 2016 Jul 1;197(1):233-43. doi: 10.4049/jimmunol.1502115. Epub 2016 Jun 3.

Abstract

Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8(+) T cell (TCD8) functional impairment during acute viral LRI, but the role of TCD8 impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus infection induces virus-specific lung TCD8 that fail to produce effector cytokines or degranulate late postinfection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung TCD8 upregulated multiple inhibitory receptors, including PD-1, lymphocyte activation gene 3 (LAG-3), T cell Ig mucin 3, and 2B4. Moreover, coexpression of these receptors continued to increase even after viral clearance, with most virus-specific lung TCD8 expressing three or more inhibitory receptors on day 14 postinfection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and APCs, further establishing an inhibitory environment. In vitro Ab blockade revealed that multiple inhibitory receptors contribute to TCD8 impairment induced by either human metapneumovirus or influenza virus infection. In vivo blockade of T cell Ig mucin 3 signaling failed to enhance TCD8 function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored TCD8 effector functions but increased lung pathology, indicating that LAG-3 mediates lung TCD8 impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung TCD8 functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung TCD8 impairment may prevent immunopathology but also contributes to recurrent lung infections.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Lung / immunology*
  • Lung / virology
  • Metapneumovirus / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mucin-3 / metabolism
  • Orthomyxoviridae Infections / immunology*
  • Paramyxoviridae Infections / immunology*
  • Programmed Cell Death 1 Receptor / genetics
  • Respiratory Tract Infections / immunology*
  • Respiratory Tract Infections / virology
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Family / metabolism

Substances

  • Antigens, CD
  • CD223 antigen
  • Cd244a protein, mouse
  • Mucin-3
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Signaling Lymphocytic Activation Molecule Family