As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1. Display omitted •Enhanced activating histone marks on IL2Rβ and BCL2 genes in cNK cells from ECs•Elevated levels of IL-15 transcription in myeloid DCs from ECs•Improved survival and increased cytotoxicity in cNK cells after IL-15 stimulation•Increased glycolytic activities in cNK cells from ECs after IL-15 stimulation Hartana et al. observed elevated IL-15 responsiveness of cNK cells from HIV-1 elite controllers, paired with increased levels of IL-15 transcription in mDCs. These results suggest that immune crosstalk between mDCs and cNK cells results in distinct IL-15 response signatures and may contribute to drug-free control of HIV-1 replication.