Cutting Edge: Heterogeneity in Cell Age Contributes to Functional Diversity of NK Cells

Heterogeneity among naive adaptive lymphocytes determines their individual functions and fate decisions during an immune response. NK cells are innate lymphocytes capable of generating "adaptive" responses during infectious challenges. However, the factors that govern various NK cell functions are not fully understood. In this study, we use a reporter mouse model to permanently "time stamp" NK cells and type 1 innate lymphoid cells (ILC1s) to characterize the dynamics of their homeostatic turnover. We found that the homeostatic turnover of tissue-resident ILC1s is much slower than that of circulating NK cells. NK cell homeostatic turnover is further accelerated without the transcription factor Eomes. Finally, heterogeneity in NK cell age diversifies NK cell function, with "older" NK cells exhibiting more potent IFN-γ production to activating stimuli and more robust adaptive responses during CMV infection. These results provide insight into how the functional response of an NK cell varies over its lifespan.