Allelic Variation of KIR and HLA Tunes the Cytolytic Payload and Determines Functional Hierarchy of NK Cell Repertoires.

The functionality of natural killer (NK) cells is tuned during education and associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation of KIR and HLA, which is known to influence the functional strength of NK cells, fine tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA-class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but was stable over time in each individual and genetically determined by allelic variation in HLA-class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as a robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of MHC-deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells resulting in predictable hierarchies in global NK cell function.