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. IMPORTANCE 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.