Homeostatic Control of Memory Cell Progenitors in the Natural Killer Cell Lineage

Recent studies have demonstrated that natural killer (NK) cells are able to undergo clonal expansion and contraction and to generate self-renewing memory cells after infection with mouse cytomegalovirus (MCMV). It is unclear whether all or only certain subsets preferentially contribute to the generation of memory NK cells. Here, we show that memory NK cells predominantly arise from killer cell lectin-like receptor G1 (KLRG1)-negative NK cell progenitors, whereas KLRG1-positive NK cells have limited capacity for expansion during infection with MCMV. Unexpectedly, the frequency of KLRG1-positive NK cells is significantly affected by the presence of T cells in the host and potentially by the host microbiota. Our findings demonstrate that excessive availability of interleukin (IL)-15 may erode the pool of memory progenitors, resulting in the decreased efficiency of memory generation in the NK cell lineage. [Display omitted] •CMV-specific memory NK cells arise from KLRG1-negative progenitors•Host microbiota and T cells regulate the memory NK cell progenitor pool•Excess IL-15 drives terminal differentiation and depletes memory NK cell progenitors Kamimura and Lanier report that memory NK cells arise from KLRG1-negative progenitors, which are regulated by host microbiota and T cells. Competition between NK cells and T cells for IL-15 prevents depletion of the memory NK cell progenitor pool.