The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation

Yusuke Sakai, Yoshihiko Tanaka, Toyoshi Yanagihara, Mayuki Watanabe, Xuefeng Duan, Masao Terasawa, Akihiko Nishikimi, Fumiyuki Sanematsu, Yoshinori Fukui

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Natural killer (NK) cells play an important role in protective immunity against viral infection and tumor progression, but they also contribute to rejection of bone marrow grafts via contact-dependent cytotoxicity. Ligation of activating NK receptors with their ligands expressed on target cells induces receptor clustering and actin reorganization at the interface and triggers polarized movement of lytic granules to the contact site. Although activation of the small GTPase Rac has been implicated in NK cell–mediated cytotoxicity, its precise role and the upstream regulator remain elusive. Here, we show that DOCK2, an atypical guanine nucleotide exchange factor for Rac, plays a key role in NK cell–mediated cytotoxicity. We found that although DOCK2 deficiency in NK cells did not affect conjugate formation with target cells, DOCK2-deficienct NK cells failed to effectively kill leukemia cells in vitro and major histocompatibility complex class I–deficient bone marrow cells in vivo, regardless of the sorts of activating receptors. In DOCK2-deficient NK cells, NKG2D-mediated Rac activation was almost completely lost, resulting in a severe defect in the lytic synapse formation. Similar results were obtained when the Rac guanine nucleotide exchange factor activity of DOCK2 was selectively abrogated. These results indicate that DOCK2-Rac axis controls NK cell–mediated cytotoxicity through the lytic synapse formation.

Original languageEnglish
Pages (from-to)386-393
Number of pages8
JournalBlood
Volume122
Issue number3
DOIs
Publication statusPublished - Jul 18 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Sakai, Y., Tanaka, Y., Yanagihara, T., Watanabe, M., Duan, X., Terasawa, M., Nishikimi, A., Sanematsu, F., & Fukui, Y. (2013). The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation. Blood, 122(3), 386-393. https://doi.org/10.1182/blood-2012-12-475897