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.