DNAM-1 Expression Marks an Alternative Program of NK Cell Maturation

Highlights•The activating receptor DNAM-1 identifies two distinct NK cell functional subsets•DNAM-1+ NKs have enhanced IL-15 signaling and are a higher producer of cytokines•DNAM-1− NKs are higher producers of MIP1 chemokines•DNAM-1+ NKs differentiate into DNAM-1− NKs through an alternative maturation pathwaySummaryNatural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1+ and DNAM-1− NK cells. DNAM-1+ NK cells produce high levels of inflammatory cytokines, have enhanced interleukin 15 signaling, and proliferate vigorously. By contrast, DNAM-1− NK cells that differentiate from DNAM-1+ NK cells have greater expression of NK-cell-receptor-related genes and are higher producers of MIP1 chemokines. Collectively, our data reveal the existence of a functional program of NK cell maturation marked by DNAM-1 expression.Graphical abstract