Indirect CD4 T cell protection against mouse gamma-herpesvirus infection via interferon gamma.

Unlabelled: CD4 T cells play a key role in γ-herpesvirus infection control. However, the mechanisms involved are unclear. Murine herpesvirus type 4 (MuHV-4) allows relevant immune pathways to be dissected experimentally in mice. In the lungs, it colonizes myeloid cells, which can express MHC class II (MHCII), and type 1 alveolar epithelial cells (AEC1), which lack it. Nevertheless, CD4 T cells can control AEC1 infection, and this control depends on MHCII expression in myeloid cells. Interferon-gamma (IFNγ) is a major component of CD4 T cell-dependent MuHV-4 control. Here, we show that the action of IFNγ is also indirect, as CD4 T cell-mediated control of AEC1 infection depended on IFNγ receptor (IFNγR1) expression in CD11c cells. Indirect control also depended on natural killer (NK) cells. Together, the data suggest that the activation of MHCII CD11c antigen-presenting cells is key to the CD4 T cell/NK cell protection axis. By contrast, CD8 T cell control of AEC1 infection appeared to operate independently.

Importance: CD4 T cells are critical for the control of gamma-herpesvirus infection; they act indirectly, by recruiting natural killer (NK) cells to attack infected target cells. Here, we report that the CD4 T cell/NK cell axis of gamma-herpesvirus control requires interferon-γ engagement of CD11c dendritic cells. This mechanism of CD4 T cell control releases the need for the direct engagement of CD4 T cells with virus-infected cells and may be a common strategy for host control of immune-evasive pathogens.