Integrins Influence the Size and Dynamics of Signaling Microclusters in a Pyk2-dependent Manner |
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Authors: | Maria Steblyanko Nadia Anikeeva Kerry S Campbell James H Keen Yuri Sykulev |
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Institution: | From the Departments of ‡Microbiology and Immunology and ;¶Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and ;the §Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 |
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Abstract: | Integrin engagement on lymphocytes initiates “outside-in” signaling that is required for cytoskeleton remodeling and the formation of the synaptic interface. However, the mechanism by which the “outside-in” signal contributes to receptor-mediated intracellular signaling that regulates the kinetics of granule delivery and efficiency of cytolytic activity is not well understood. We have found that variations in ICAM-1 expression on tumor cells influence killing kinetics of these cells by CD16.NK-92 cytolytic effectors suggesting that changes in integrin ligation on the effector cells regulate the kinetics of cytolytic activity by the effector cells. To understand how variations of the integrin receptor ligation may alter cytolytic activity of CD16.NK-92 cells, we analyzed molecular events at the contact area of these cells exposed to planar lipid bilayers that display integrin ligands at different densities and activating CD16-specific antibodies. Changes in the extent of integrin ligation on CD16.NK-92 cells at the cell/bilayer interface revealed that the integrin signal influences the size and the dynamics of activating receptor microclusters in a Pyk2-dependent manner. Integrin-mediated changes of the intracellular signaling significantly affected the kinetics of degranulation of CD16.NK-92 cells providing evidence that integrins regulate the rate of target cell destruction in antibody-dependent cell cytotoxicity (ADCC). |
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Keywords: | cellular immune response immunology lymphocyte natural killer cells (NK cells) signaling ADCC Cytotoxic lymphocytes Integrin receptors signaling microclusters killing kinetics |
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