Abstract Cytomegalovirus (CMV) has evolved a unique virus-host relationship in the salivary glands (SGs) to sustain prolonged viral replication and hence chances for horizontal transmission. Previous reports have established a decisive role for IFN γ producing CD4 + T cells to control murine CMV (MCMV) infection in the SGs; however, micro-anatomical information regarding their mode of action is largely missing. Here, we provide a spatiotemporal analysis of defined antiviral immune actions that eventually culminate in control of lytic MCMV replication in this preferred mucosal niche. CXCR3-mediated guidance of CD4 + T cells towards CXCL9 and CXCL10 expressing cells resulted in discrete clusters close to infection foci where they reported TCR engagement and produced IFN γ . Of note, these clusters occasionally contained CD11c + antigen-presenting cells with engulfed virus-associated remnants, most likely apoptotic bodies derived from previously infected cells, enabling antigen presentation to CD4 + T cells. The induced IFN γ production within these CD4 + T cell accumulations triggered IFN γ R signaling in a confined perimeter, thereby inducing local, but not organ-wide protection, and allowing MCMV replication to continue at not yet protected sites. Combining experimental data with a mathematical model of the spatiotemporal dynamics of infection and CD4 + T cell dynamics revealed a scenario, in which ultimate MCMV control is achieved through accumulating sites of regionally-confined tissue protection.

Locally confined IFNγ production by CD4+ T cells provides niches for murine cytomegalovirus replication in the salivary gland