title: The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation.
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.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakai
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Yanagihara
authors.forename: Mayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Duan
authors.forename: Masao
authors.initials: M
authors.lastname: Terasawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D054992:Immunological Synapses / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D015395:Histocompatibility Antigens Class I; D019869:Phosphatidylinositol 3-Kinases; D020744:rac GTP-Binding Proteins; C471356:DOCK2 protein, mouse