SLAMF7 selectively favors degranulation to promote cytotoxicity in human NK cells

NK cells play an important role in immunity by recognizing and eliminating cells undergoing infection or malignant transformation. This role is dependent on the ability of NK cells to lyse targets cells in a perforin‐dependent mechanism and by secreting inflammatory cytokines. Both effector functions are controlled by several cell surface receptors. The Signaling Lymphocyte Activation Molecule (SLAM) family of receptors plays an essential role in regulating NK cell activation. Several studies have demonstrated that SLAMF7 regulates NK cell activation. However, the molecular and cellular mechanisms by which SLAMF7 influences NK effector functions are unknown. Here, we present evidence that physiological ligation of SLAMF7 in human NK cells enhances the lysis of target cells expressing SLAMF7. This effect was dependent on the ability of SLAMF7 to promote NK cell degranulation rather than cytotoxic granule polarization or cell adhesion. Moreover, SLAMF7‐dependent NK cell degranulation was predominantly dependent on PLC‐γ when compared to PI3K. These data provide novel information on the cellular mechanism by which SLAMF7 regulates human NK cell activation. Finally, this study supports a model for NK cell activation where activated receptors contribute by regulating specific discrete cellular events rather than multiple cellular processes. SLAMF7 enhances human NK cell activation by promoting lytic granule exocytosis rather than lytic granule polarization or cell adhesion. This effect was predominantly dependent on PLC‐γ. This study supports a model for NK cell activation where activating receptors contribute by regulating specific discrete cellular events rather than multiple cellular processes.