CD56 regulates human NK cell cytotoxicity through Pyk2

Abstract

Human natural killer (NK) cells are defined as CD56+CD3−. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstrate that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 is decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 are rescued by the reintroduction of CD56. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells.

Synergistic Tumor Cytolysis by NK Cells in Combination With a Pan-HDAC Inhibitor, Panobinostat

“…Although there appears to be relatively low surface expression of other activating receptors, we found an enhanced expression of CD56 (cell adhesion surface receptors) that play an important role in cell-cell contact for panobinostat-treated NK(YTS) cells relative to control. Our data is consistent with earlier reports showing the importance of CD56 –neural cell adhesion molecule (NCAM) ( 60 ). CD56 (NCAM) expression on NK cells has been shown to induce activation signals via adhesion molecules, as well as an increase in cytotoxicity and phosphorylation of the human NK cell signaling cascade ( 60 ).…”

“…Our data is consistent with earlier reports showing the importance of CD56 –neural cell adhesion molecule (NCAM) ( 60 ). CD56 (NCAM) expression on NK cells has been shown to induce activation signals via adhesion molecules, as well as an increase in cytotoxicity and phosphorylation of the human NK cell signaling cascade ( 60 ). Also, CD56 expression –similar to CD69 and HLA-DR expression –has been shown as an activation marker of NK cells with enhanced cytotoxicity ( 61 ).…”

High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome

“…Expansion of CD56 − CD16 + NK cells is mainly observed in viral noncontrollers ( 19 , 20 ). Indeed, CD56 is an important adhesion molecule involved in NK cell development, motility, and pathogen recognition ( 22 – 27 ). CD56 is also required for the formation of the immunological synapse between NK cells and target cells, lytic functions, and cytokine production ( 26 , 28 ).…”

“…Indeed, CD56 is an important adhesion molecule involved in NK cell development, motility, and pathogen recognition ( 22 – 27 ). CD56 is also required for the formation of the immunological synapse between NK cells and target cells, lytic functions, and cytokine production ( 26 , 28 ). As a consequence, CD56 − CD16 + NK cells display lower degranulation capacities and decreased expression of triggering receptors, perforin, and granzyme B, dramatically reducing their cytotoxic potential, notably against tumor target cells ( 2 , 19 , 20 , 29 , 30 ).…”

A Functional Chemiluminescent Probe for in Vivo Imaging of Natural Killer Cell Activity Against Tumours

“…Next, we prepared in vitro cocultures of human NK-92 cells and the human breast adenocarcinoma cell line MDA-MB-231. Given previous reports of NK cell-based cytotoxicity assays, [47,48] NK-92 cells and MDA-MB-231 cells were co-cultured in a 8:1 ratio and in the presence of interleukin-2 (IL-2), an essential cytokine for the survival, proliferation and activation of NK-92 cells. [49] Under these conditions, NK-92 cells induced apoptosis of MDA-MB-231 cancer cells, as shown by fluorescence microscopy using a caspase 3 marker (Supplementary Figure 5).…”