Human peripheral blood DNAM-1neg 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 NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56 and CD56DNAM-1 NK cell subsets, CD56DNAM-1 NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56DNAM-1 NK cells impaired CD56DNAM-1 NK cell-mediated killing, indicating a potential inhibitory role for the CD56DNAM-1 NK cell subset. Transcriptome analysis revealed that CD56DNAM-1 NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56DNAM-1 NK cells were found to differentiate from CD56DNAM-1 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 CD56DNAM-1/CD56DNAM-1 NK cell ratios and reduced cytotoxic activity of CD56DNAM-1 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