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.
Highlights
The immune response against CMV infection in humans and murine cytomegalovirus (MCMV) in mice has been studied for decades [1]
In this study we focused on Murine CMV (MCMV) infection in adult mouse lungs and found that, in the immunocompetent host, immune cells infiltrate the lung tissue as nodular inflammatory foci that help to control the acute infection in one week
Following infection of lungs in neonatal mice, we previously showed that MCMV infection can be precisely characterized, revealing the formation of dynamic nodular inflammatory foci (NIF) with accumulation of virus-infected and immune cells [26,27]
Summary
The immune response against CMV infection in humans and murine cytomegalovirus (MCMV) in mice has been studied for decades [1]. In patients that suffer from CMV reactivation or primary infection during periods of severe immunosuppression, the infusion of donor HCMVspecific T cells was found to improve the control of infection [7,8] It remains unclear how CD8 T cells are able to control CMV infection, given that both HCMV and MCMV encode for proteins that efficiently down-modulate surface major histocompatibility complex class I (MHCI) on infected cells [9]. This immune evasion mechanism can prevent virus-specific T cells from recognizing their target cells and interferes with CD8 T cellmediated killing [10]. Other immunoevasins interfere with the presentation of antigen via major histocompatibility complex class II (MHCII) molecules to avoid recognition by CD4 T cells [11,12] but they downregulate ligands of natural killer (NK) cell receptors to avoid cytotoxic killing [13]
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