Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs

PLoS Pathog. 2014 Apr 24;10(4):e1004100. doi: 10.1371/journal.ppat.1004100. eCollection 2014 Apr.

Abstract

The lungs are a noted predilection site of acute, latent, and reactivated cytomegalovirus (CMV) infections. Interstitial pneumonia is the most dreaded manifestation of CMV disease in the immunocompromised host, whereas in the immunocompetent host lung-infiltrating CD8 T cells confine the infection in nodular inflammatory foci and prevent viral pathology. By using murine CMV infection as a model, we provide evidence for a critical role of mast cells (MC) in the recruitment of protective CD8 T cells to the lungs. Systemic infection triggered degranulation selectively in infected MC. The viral activation of MC was associated with a wave of CC chemokine ligand 5 (CCL5) in the serum of C57BL/6 mice that was MC-derived as verified by infection of MC-deficient Kit(W-sh/W-sh) "sash" mutants. In these mutants, CD8 T cells were recruited less efficiently to the lungs, correlating with enhanced viral replication and delayed virus clearance. A causative role for MC was verified by MC reconstitution of "sash" mice restoring both, efficient CD8 T-cell recruitment and infection control. These results reveal a novel crosstalk axis between innate and adaptive immune defense against CMV, and identify MC as a hitherto unconsidered player in the immune surveillance at a relevant site of CMV disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / pathology
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Mast Cells / immunology*
  • Mast Cells / pathology
  • Mice
  • Mice, Mutant Strains
  • Muromegalovirus / immunology*
  • Muromegalovirus / metabolism
  • Pneumonia, Viral / genetics
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft, Collaborative Research Center (SFB) 490, individual projects E3 (SE, VB, and RH) and E2 (MJR), the Clinical Research Group KFO 183 (NAWL, JKB, and MJR), and Priority Program SPP1394, individual project STA 984/4-1 (MS). NAWL received intramural funding in the young investigator program MAIFOR of the University Medical Center, Mainz, Germany, and RH received intramural funding in program IFF-I of the Johannes Gutenberg-University, Mainz, Germany. JKB was awarded a scholarship from the Research Center for Immunology (Forschungzentrum Immunologie, FZI) at the University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.