Human peripheral blood DNAM-1^neg NK cells are a terminally differentiated subset with limited effector functions

Natural killer (NK) cells are a heterogeneous population of innate lymphocytes whose potent anticancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell diversity in antitumor responses has hindered advances in this area. In this study, we describe a new CD56^dim NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56^bright and CD56^dimDNAM-1^pos NK cell subsets, CD56^dimDNAM-1^neg NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56^dimDNAM-1^neg NK cells impaired CD56^dimDNAM-1^pos NK cell-mediated killing, indicating a potential inhibitory role for the CD56^dimDNAM-1^neg NK cell subset. Transcriptome analysis revealed that CD56^dimDNAM-1^neg NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56^dimDNAM-1^neg NK cells were found to differentiate from CD56^dimDNAM-1^pos NK cells. Finally, we report a dysregulation of NK cell subsets in the blood of patients diagnosed with Hodgkin lymphoma and diffuse large B-cell lymphoma, characterized by decreased CD56^dimDNAM-1^pos/CD56^dimDNAM-1^neg NK cell ratios and reduced cytotoxic activity of CD56^dimDNAM-1^pos NK cells. Altogether, our data offer a better understanding of human peripheral blood NK cell populations and have important clinical implications for the design of NK cell-targeting therapies.