Control of primary mouse cytomegalovirus infection in lung nodular inflammatory foci by cooperation of interferon-gamma expressing CD4 and CD8 T cells

PLoS Pathog. 2018 Aug 28;14(8):e1007252. doi: 10.1371/journal.ppat.1007252. eCollection 2018 Aug.

Abstract

Human cytomegalovirus (CMV) and mouse cytomegalovirus (MCMV) infection share many characteristics. Therefore infection of mice with MCMV is an important tool to understand immune responses and to design vaccines and therapies for patients at the risk of severe CMV disease. In this study, we investigated the immune response in the lungs following acute infection with MCMV. We used multi-color fluorescence microscopy to visualize single infected and immune cells in nodular inflammatory foci (NIFs) that formed around infected cells in the lungs. These NIFs consisted mainly of myeloid cells, T cells, and some NK cells. We found that the formation of NIFs was essential to reduce the number of infected cells in the lung tissue, showing that NIFs were sites of infection as well as sites of immune response. Comparing mice deficient for several leukocyte subsets, we identified T cells to be of prime importance for restricting MCMV infection in the lung. Moreover, T cells had to be present in NIFs in high numbers, and CD4 as well as CD8 T cells supported each other to efficiently control virus spread. Additionally, we investigated the effects of perforin and interferon-gamma (IFNγ) on the virus infection and found important roles for both mechanisms. NK cells and T cells were the major source for IFNγ in the lung and in in vitro assays we found that IFNγ had the potential to reduce plaque growth on primary lung stromal cells. Notably, the T cell-mediated control was shown to be perforin-independent but IFNγ-dependent. In total, this study systematically identifies crucial antiviral factors present in lung NIFs for early containment of a local MCMV infection at the single cell level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / physiology*
  • DNA-Binding Proteins / genetics
  • Herpesviridae Infections / complications
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / pathology
  • Immunity, Cellular / physiology
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / immunology*
  • Pneumonia / immunology
  • Pneumonia / pathology
  • Pneumonia / virology*

Substances

  • DNA-Binding Proteins
  • Rag2 protein, mouse
  • Interferon-gamma

Grants and funding

This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB900-B1 to RF and MM, by Deutsches Zentrum für Infektionsforschung (DZIF) grant DZIF 07.001‐Stahl to FRS, the Hannover Biomedical Research School (HBRS) and the Center for Infection Biology (ZIB) both to YL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.