CD4 T Cells Control Murine Cytomegalovirus Infection Indirectly.

CD4 T cells are key to controlling cytomegalovirus infections. Salivary gland infection by murine cytomegalovirus (MCMV) provides a way to identify mechanisms. CD11c dendritic cells (DC) disseminate MCMV to the salivary glands, where they transfer infection to acinar cells. Antiviral CD4 T cells are often considered to be directly cytotoxic for cells expressing major histocompatibility complex class II (MHCII). However, persistently infected salivary gland acinar cells are MHCII and are presumably inaccessible to direct CD4 T cell recognition. Here, we show that CD4 T cell depletion amplified infection of MHCII acinar cells but not MHCII cells. MCMV-infected mice with disrupted MHCII on CD11c cells showed increased MHCII acinar infection; antiviral CD4 T cells were still primed, but their recruitment to the salivary glands was reduced, suggesting that engagement with local MHCII DC is important for antiviral protection. As MCMV downregulates MHCII on infected DC, the DC participating in CD4 protection may thus be uninfected. NK cells and gamma interferon (IFN-γ) may also contribute to CD4 T cell-dependent virus control: CD4 T cell depletion reduced NK cell recruitment to the salivary glands, and both NK cell and IFN-γ depletion equalized infection between MHCII-disrupted and control mice. Taken together, these results suggest that CD4 T cells protect indirectly against infected acinar cells in the salivary gland via DC engagement, requiring the recruitment of NK cells and the action of IFN-γ. Congruence of these results with an established CD4 T cell/NK cell axis of gammaherpesvirus infection control suggests a common mode of defense against evasive viruses. Cytomegalovirus infections commonly cause problems in immunocompromised patients and in pregnancy. We lack effective vaccines. CD4 T cells play an important role in normal infection control, yet how they act has been unknown. Using murine cytomegalovirus as an accessible model, we show that CD4 T cells are unlikely to recognize infected cells directly. We propose that CD4 T cells interact with uninfected cells that present viral antigens and recruit other immune cells to attack infected targets. These data present a new outlook on understanding how CD4 T cell-directed control protects against persistent cytomegalovirus infection.