Functional Maturation Development Enhances KIR Expression and Notch Signaling at Later Stages of NK Cell

The Notch signaling pathway plays a substantial role in human NK cell development. However, the role of Notch on killer Ig–like receptor (KIR) upregulation and acquisition of effector function has not been explored. To evaluate how Notch influences terminal differentiation , cord blood–derived NK cells or sorted peripheral blood NK cells were cultured with IL-15 for 7 d with inhibitory or activating Notch signals. Inhibition of Notch signaling significantly decreased KIR expression, whereas activation enhanced it. Overexpression of activated Notch on cord blood–derived NK cells resulted in a 2-fold increase in KIR expression, indicating that Notch signaling plays a direct, cell-intrinsic role in KIR regulation. Moreover, Notch-mediated KIR expression on NK cells is regulated through cis inhibition by delta-like ligand 1. Notch signaling also enhances CD16 upregulation that precedes KIR expression. Concomitant with the upreg-ulation of KIR and CD16, Notch signaling induces increased cytolytic effector capacity and cytokine secretion, even in posttransplant samples in which NK cell function is inherently defective. Given these attributes of Notch signaling, we propose that Notch agonists may enhance NK cell maturation and tumor killing in a posttransplant setting. N atural killer cells are a critical component of the immune system, where they play a role in viral responses and tumor control. Human NK cells develop from CD34 + hematopoietic stem cells (HSCs) and must traverse through a number of developmental stages prior to acquisition of CD56 expression and functional competence (1). NK cell commitment is marked by CD56 expression that can be divided further into two populations of NK cells based on CD56 intensity, with the CD56 bright NK cells preceding, and giving rise to, the CD56 dim NK cells (2, 3). CD56 dim NK cells are thought to be more functionally mature with greater cytotoxic capacity and cytokine production after target cell recognition (4–6). Acquisition of inhibitory killer Ig–like receptor (KIR) expression occurs progressively during development within the CD56 dim NK cell subset and results in increased function, driving NK cell education or licensing (7–10). Although some of the components necessary for KIR expression on NK cells have been elucidated (11–13), many questions remain concerning which signaling pathways are involved in KIR expression and functional maturation of NK cells. The Notch signaling pathway has been shown to have a role in the development and function of the innate and adaptive immune system (14). Early mouse experiments showed that Jagged2, a Notch ligand, was …