Orr Mark T, Sun Joseph C, Hesslein David G T, Arase Hisashi, Phillips Joseph H, Takai Toshiyuki, Lanier Lewis L
Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, 94143, USA.
J Exp Med. 2009 Apr 13;206(4):807-17. doi: 10.1084/jem.20090168. Epub 2009 Mar 30.
The activating natural killer (NK) cell receptor Ly49H recognizes the mouse cytomegalovirus (MCMV) m157 glycoprotein expressed on the surface of infected cells and is required for protection against MCMV. Although Ly49H has previously been shown to signal via DAP12, we now show that Ly49H must also associate with and signal via DAP10 for optimal function. In the absence of DAP12, DAP10 enables Ly49H-mediated killing of m157-bearing target cells, proliferation in response to MCMV infection, and partial protection against MCMV. DAP10-deficient Ly49H(+) NK cells, expressing only Ly49H-DAP12 receptor complexes, are partially impaired in their ability to proliferate during MCMV infection, display diminished ERK1/2 activation, produce less IFN-gamma upon Ly49H engagement, and demonstrate reduced control of MCMV infection. Deletion of both DAP10 and DAP12 completely abrogates Ly49H surface expression and control of MCMV infection. Thus, optimal NK cell-mediated immunity to MCMV depends on Ly49H signaling through both DAP10 and DAP12.
活化性自然杀伤（NK）细胞受体Ly49H可识别在受感染细胞表面表达的小鼠巨细胞病毒（MCMV）m157糖蛋白，是抵御MCMV所必需的。尽管此前已证明Ly49H通过DAP12进行信号传导，但我们现在表明，Ly49H还必须与DAP10结合并通过其进行信号传导才能发挥最佳功能。在没有DAP12的情况下，DAP10可使Ly49H介导对携带m157的靶细胞的杀伤、对MCMV感染作出反应的增殖以及对MCMV的部分保护。缺乏DAP10的Ly49H(+) NK细胞仅表达Ly49H-DAP12受体复合物，其在MCMV感染期间增殖的能力部分受损，ERK1/2活化减弱，Ly49H激活后产生的干扰素-γ减少，并表现出对MCMV感染的控制减弱。DAP10和DAP12均缺失会完全消除Ly49H的表面表达以及对MCMV感染的控制。因此，NK细胞介导的针对MCMV的最佳免疫取决于Ly49H通过DAP10和DAP12两者进行的信号传导。
