Genetic influence on splenic natural killer cell frequencies and maturation among aged mice

Natural killer (NK) cells are cytotoxic innate lymphocytes that are integral to host defenses against viruses and neoplastic cells. Aging causes phenotypic and functional impairment of NK cells, which diminishes innate immune surveillance, yet the factors that determine the aged NK cell phenotype have not been completely defined. For instance, the genetic basis of the aged NK cell phenotype has not been established, but if determined, could highlight important genetic regulators of NK cells later in life. In this study, we estimated the heritability of splenic NK cell frequencies in aged mice from 15 classical and four wild-derived inbred strains. Our data suggest that frequencies of total (NKp46⁺CD3^-) NK and mature (NKp46⁺CD3^-CD11b⁺CD27^-) NK cells were highly heritable at old age, and that total NK cell frequencies were independent predictors of median strain life spans. Strains with divergent phenotypes were compared to young-adult controls, and trends of age-related NK cell phenotypic alterations were confirmed. Finally, in silico mapping techniques revealed candidate genes associated with the aged NK cell phenotype. To our knowledge, these results are the first to demonstrate the genetic basis of the aged NK cell phenotype and will inform future mechanistic studies of NK cell dysfunction during aging.