Ly6Chi monocytes balance regulatory and cytotoxic CD4 T cell responses to control virus-induced immunopathology

Gammaherpesviruses have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of gammaherpesviruses in hosts appears to broadly shape host immunity. Here, we show that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse gammaherpesvirus, drives the recruitment of Ly6Chi monocytes into the airway, thereby modulating the host immune response. The absence of Ly6Chi monocytes is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4–imprinted monocytes recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi monocytes in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections.