The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation
The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation
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DOI：
10.1182/blood-2012-12-475897
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发表时间：
2013-07-18
期刊：
影响因子：
20.3
通讯作者：
Fukui, Yoshinori
中科院分区：
文献类型：
--
作者：
Sakai, Yusuke;Tanaka, Yoshihiko;Fukui, Yoshinori
自然杀伤（NK）细胞在针对病毒感染和肿瘤进展的保护性免疫中发挥重要作用，但它们也通过接触依赖性细胞毒性导致骨髓移植物排斥。激活NK受体与其在靶细胞上表达的配体的连接诱导受体聚集和肌动蛋白在界面处的重组，并触发溶解颗粒向接触位点的极化运动。尽管小GTdR ac的激活与NK细胞介导的细胞毒性有关，但其确切作用和上游调节因子仍然难以捉摸。在这里，我们表明，DOCK 2，一种非典型的鸟嘌呤核苷酸交换因子的Rac，在NK细胞介导的细胞毒性中起着关键作用。我们发现，尽管NK细胞中DOCK 2缺陷不影响与靶细胞的结合物形成，但DOCK 2缺陷的NK细胞在体外不能有效地杀死白血病细胞，在体内不能有效地杀死主要组织相容性复合物I类缺陷的骨髓细胞，无论激活受体的种类如何。在DOCK 2缺陷型NK细胞中，NKG 2D介导的Rac激活几乎完全丧失，导致溶解性突触形成严重缺陷。当选择性地消除DOCK 2的Rac鸟嘌呤核苷酸交换因子活性时，获得了类似的结果。这些结果表明，DOCK 2-Rac轴通过溶解性突触形成控制NK细胞介导的细胞毒性。
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.