Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity

H Ham, S Guerrier, JJ Kim, RA Schoon… - The Journal of …, 2013 - journals.aai.org
H Ham, S Guerrier, JJ Kim, RA Schoon, EL Anderson, MJ Hamann, Z Lou, DD Billadeau
The Journal of Immunology, 2013journals.aai.org
Recently, patients with mutations in DOCK8 have been reported to have a combined
immunodeficiency characterized by cutaneous viral infections and allergies. NK cells
represent a first-line defense against viral infections, suggesting that DOCK8 might
participate in NK cell function. In this study, we demonstrate that DOCK8-suppressed human
NK cells showed defects in natural cytotoxicity as well as specific activating receptor-
mediated NK cytotoxicity. Additionally, compared with control NK cells, NK cells depleted of …
Abstract
Recently, patients with mutations in DOCK8 have been reported to have a combined immunodeficiency characterized by cutaneous viral infections and allergies. NK cells represent a first-line defense against viral infections, suggesting that DOCK8 might participate in NK cell function. In this study, we demonstrate that DOCK8-suppressed human NK cells showed defects in natural cytotoxicity as well as specific activating receptor-mediated NK cytotoxicity. Additionally, compared with control NK cells, NK cells depleted of DOCK8 showed defective conjugate formation, along with decreased polarization of LFA-1, F-actin, and cytolytic granules toward the cytotoxic synapse. Using a proteomic approach, we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion. Taken together, our results demonstrate an important role for DOCK8 in NK cell effector function and provide important new mechanistic insight into how DOCK8 regulates F-actin and integrin-mediated adhesion in immune cells.
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