Regulatory T Cells Expressing Granzyme B Play a Critical Role in Controlling Lung Inflammation During Acute Viral Infection

Mucosal Immunol. 2012 Mar;5(2):161-72. doi: 10.1038/mi.2011.62. Epub 2012 Jan 11.

Abstract

The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described "depletion of regulatory T cell" (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antibodies / metabolism
  • Antigen-Antibody Complex / administration & dosage
  • Bronchiolitis, Viral / etiology
  • Bronchiolitis, Viral / immunology*
  • Bronchiolitis, Viral / prevention & control
  • Cell Movement / drug effects
  • Cells, Cultured
  • Child
  • Disease Models, Animal
  • Disease Progression
  • Granzymes / genetics
  • Granzymes / immunology
  • Granzymes / metabolism*
  • Humans
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Lymphocyte Depletion
  • Mice
  • Pneumonia, Viral / immunology*
  • Respiratory Syncytial Virus Infections / complications
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / therapy
  • Respiratory Syncytial Viruses / immunology*
  • Respiratory Syncytial Viruses / pathogenicity
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • T-Lymphocytes, Regulatory / virology
  • Viral Load / drug effects
  • Viral Load / immunology

Substances

  • Antibodies
  • Antigen-Antibody Complex
  • Interleukin-2
  • Granzymes