Licensed NK Cell Responses to Acute Viral Infection Shape Priming and Differentiation of CD8+ T cells

Natural killer (NK) cells represent a critical first-line of immune defense against a bevy of viral pathogens, and infection can provoke them to mediate both supportive and suppressive effects on virus-specific adaptive immunity. Previous studies have shown that licensed Ly49G2+ NK cells confer murine (M)CMV resistance in mice expressing MHC I Dk , a specific ligand of the inhibitory Ly49G2 receptor, which results in enhanced adaptive immunity due to accelerated accumulation of virus-specific CD8+ T cells. However, relatively little is known about the licensed NK-cell effect on T cell priming or ensuing effector and memory T-cell responses. We found that CD8+ T cell dependence on CD27 co-stimulation for early priming and differentiation is shaped by the efficiency of NK responses to virus infection. Moreover, T cell priming in the presence or absence of licensed NK cell control resulted in a profound skewing of CD8+ T cells into memory precursor effector cells (MPEC) or sustained short-lived effectors (SLEC), respectively. This T cell differentiation effect endured through viral latency such that the frequencies of memory and effector cells reflected differences observed for the strains at day 10. Transfer of virus-experienced CD8+ T cells from mice with or without licensed G2+ NK cells improved resistance against secondary challenge in naïve recipients. However, we observed distinct profiles and kinetics of resistance that likely reflected host-specific needs for distinct modes of T cell immunity. Thus specific virus control mediated by NK cells significantly impacts T cell priming, differentiation, and the manner in which T cells provide long-term protective immunity.