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

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.

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.