HUMAN PERIPHERAL BLOOD DNAM-1NEG NK CELLS ARE A TERMINALLY DIFFERENTIATED SUBSET WITH IMMUNOREGULATORY PROPERTIES

NK cells are a heterogeneous population of innate lymphocytes whose potent anti-cancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell diversity in anti-tumor responses has hindered advances in this area. In this study, we describe a new CD56dim NK cell subset characterized by the lack of expression of DNAX-accessory molecule 1 (DNAM-1). Compared with CD56bright and CD56dimDNAM-1pos NK cell subsets CD56dimDNAM-1neg NK cells displayed reduced motility, poor proliferation, lower production of IFNγ and limited killing capacities. Soluble factors secreted by CD56dimDNAM-1neg NK cells impaired CD56dimDNAM-1pos NK cell-mediated killing, indicating a potential inhibitory role for the CD56dimDNAM-1neg NK cell subset.  Transcriptome analysis revealed that CD56dimDNAM-1neg NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine-stimulation, CD56dimDNAM-1neg NK cells were found to differentiate from CD56dimDNAM-1pos 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 CD56dimDNAM-1pos/ CD56dimDNAM-1neg NK cell ratios and reduced cytotoxic activity of CD56dimDNAM-1pos 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.