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

Hyoungjun Ham, Sabrice Guerrier, Jung Jin Kim, Renee A. Schoon, Erik L. Anderson, Michael J. Hamann, Zhenkun Lou, Daniel D. Billadeau

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3661-3669
Number of pages9
JournalJournal of Immunology
Volume190
Issue number7
DOIs
StatePublished - Apr 1 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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