Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling

Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell-specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c+ dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-γ production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity. [Display omitted] •Generation of a mouse model to study DC-specific TLR9 function•cDC uses TLR9- and MyD88-dependent mechanisms to promote MCMV immunity•cDC-derived cytokines control independent NK cell effector responses against MCMV Puttur et al. generate TLR9 conditional knockout mice to understand how individual DC subsets mechanistically regulate NK cell immunity during MCMV infection. By genetically deleting TLR9 or reactivating MyD88 function in DC subsets, they demonstrate that TLR9/MyD88 signaling in cDCs choreographs early MCMV immunity, providing targets for future therapies.