Abstract
Natural killer (NK) cells are part of the innate immune response and play a crucial role in the defense against tumors and virus-infected cells. Their effector functions include the specific killing of target cells, as well as the modulation of other immune cells by cytokine release. Kinases constitute a relevant part in signaling, are prime targets in drug research and the protein kinase inhibitor Dasatinib is already used for immune-modulatory therapies. In this study, we tested the effects of the kinase inhibitors CK59 and CID755673. These inhibitors are directed against calmodulin kinase II (CaMKII; CK59) and PKD family kinases (CID755673) that were previously suggested as novel components of NK activation pathways. Here, we use a multi-parameter, FACS-based assay to validate the influence of CK59 and CID755673 on the effector functions of primary NK cells. Treatment with CK59 and CID755673 indeed resulted in a significant dose-dependent reduction of NK cell degranulation markers and cytokine release in freshly isolated Peripheral blood mononuclear cell populations from healthy blood donors. These results underline the importance of CaMKII for NK cell signaling and suggest protein kinase D2 as a novel signaling component in NK cell activation. Notably, kinase inhibition studies on pure NK cell populations indicate significant donor variations.
Highlights
Natural killer (NK) cells establish the first line of innate immune defense against pathogen-infected cells and tumor cells, as well as a certain set of hematopoietic cells (Vivier et al, 2008; Bryceson et al, 2009), a process known as natural cytotoxicity.Natural cytotoxicity encompasses coordination of following steps: contact with target cells, adhesion, synapse formation, granule polarization, and granule exocytosis
Generally NK cell activation can be subdivided into two mechanisms: CD16-mediated antibody-dependent cellular cytotoxicity (ADCC) and“natural” cytotoxicity
Whereas CD16 engagement alone is sufficient to induce prominent NK cell effector functions, natural cytotoxicity depends on the interaction between multiple activating receptors and the absence of inhibitory receptors
Summary
Natural cytotoxicity encompasses coordination of following steps: contact with target cells, adhesion, synapse formation, granule polarization, and granule exocytosis. These steps are mainly under the control of a multiplicity of germline-encoded activating and inhibitory surface receptors, which bind ligands expressed on target cells (Bryceson et al, 2006, 2011; Lanier, 2008; Pegram et al, 2010). ADCC depends on FcγRIIIA receptor expression (CD16), so that cells can become targets that do normally not activate NK effector responses (Forthal et al, 1999). Natural cytotoxicity occurs independently of antigen recognition and is mainly studied in vitro by using cell lines like K562 (Hanson et al, 2007)
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