Gene expression profile at single cell level of monocytes (MOs) and T cells from the lungs and from broncho-alveolar lavage fluids (BALF) from Mock and MuHV-4 infected WT and CCR2 KO mice.

Gammaherpesviruses (γHVs) have co-evolved with their hosts over millions of years, leading to remarkably high infection prevalence and establishment of symbiotic relationship. Therefore, the lifelong persistence of γHVs appear to broadly shape host immunity. Here, we show that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment in the airways of Ly6Chi monocytes (MOs) that control the host immune response. Indeed, the absence of those MOs elicits a severe virus-induced immunopathology associated with the systemic release of inflammatory mediators. Mechanistically, MuHV-4 imprinted MOs recruit CD4 T cells in the airways and trigger immunosuppressive signalling pathways through the PDL1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi MOs in the modulation of CD4 T cell functions, and reveal key pathways that could be targeted to interfere with the detrimental immunopathological cascade during respiratory viral infections. Lung MOs and CD4 T cells from C57BL/6 mice were isolated by Fluorescence-activated cell sorting (FACS) according to the presence or absence of surface markers.