Cytomegalovirus infection drives avidity selection of natural killer cells

Abstract Adaptive lymphocyte clones with the greatest receptor affinity tend to dominate primary and secondary immune responses. Strength of receptor signal and receptor abundance, along with competition for antigen and cytokines, drive preferential outgrowth of certain clones, shaping the effector and memory pool in selection processes known as affinity and avidity maturation. Natural killer (NK) cells are innate lymphocytes capable of “adaptive” responses following infectious challenges. However, whether NK cells undergo a similar selection process on the basis of their avidity for cognate ligand is not known. Here, we show that NK cells with a broad range of avidities for the mouse cytomegalovirus (MCMV) glycoprotein m157 are initially recruited after virus infection, but those with highest avidity are selected to undergo the greatest clonal expansion to comprise the memory NK cell population. Furthermore, pre-established levels of Ly49H receptor expression within the Ly49H+ NK cell pool dictated the functional contribution of a given NK cell during MCMV infection, with lower avidity NK cells possessing greater capacity for IFN-γ production, and higher avidity NK cells possessing greater capacity for cytotoxicity and adaptive responses. Moreover, we provide evidence for avidity selection also occurring in human NK cells during human CMV (HCMV) infection. These results provide a mechanistic understanding of how heterogeneity in NK cell avidity underlies the diversification of NK cell effector function during a primary antiviral immune response, and how the process of avidity selection may serve to produce the most potent memory NK cell pool.