A CD4+ T Cell-NK Cell Axis of Gammaherpesvirus Control.

CD4+ T cells are essential to control herpesviruses. Murid herpesvirus 4 (MuHV-4)-driven lung disease in CD4+ T-cell-deficient mice provides a well-studied example. Protective CD4+ T cells have been hypothesized to kill infected cells directly. However, removing major histocompatibility complex class II (MHCII) from LysM+ or CD11c+ cells increased MuHV-4 replication not in those cells but in type 1 alveolar epithelial cells, which lack MHCII, LysM, or CD11c. Disruption of MHCII in infected cells had no effect. Therefore, CD4+ T cells engaged uninfected presenting cells and protected indirectly. Mice lacking MHCII in LysM+ or CD11c+ cells maintained systemic antiviral CD4+ T cell responses, but recruited fewer CD4+ T cells into infected lungs. NK cell infiltration was also reduced, and NK cell depletion normalized infection between MHCII-deficient and control mice. Therefore, NK cell recruitment seemed to be an important component of CD4+ T-cell-dependent protection. Disruption of viral CD8+ T cell evasion made this defense redundant, suggesting that it is important mainly to control CD8-evasive pathogens.IMPORTANCE Gammaherpesviruses are widespread and cause cancers. CD4+ T cells are a key defense. We found that they defend indirectly, engaging uninfected presenting cells and recruiting innate immune cells to attack infected targets. This segregation of CD4+ T cells from immediate contact with infection helps the immune system to cope with viral evasion. Priming this defense by vaccination offers a way to protect against gammaherpesvirus-induced cancers.