Characterization of murine cytomegalovirus m157 from infected cells and identification of critical residues mediating recognition by the NK cell receptor Ly49H
Characterization of murine cytomegalovirus m157 from infected cells and identification of critical residues mediating recognition by the NK cell receptor Ly49H
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DOI：
10.4049/jimmunol.181.1.265
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发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Heusel, Jonathan W.
中科院分区：
文献类型：
--
作者：
Davis, Aja H.;Guseva, Natalya V.;Heusel, Jonathan W.
活化的NK细胞介导有效的细胞溶解和分泌效应功能，是早期抗病毒免疫反应的重要组成部分。NK细胞的活性受抑制受体的调控，抑制受体识别健康细胞上表达的MHC I类配体，激活受体识别可诱导宿主配体或未被很好表征的配体。小鼠NK细胞的活化Ly49H受体是独特的，因为它特异性识别病毒编码的配体，小鼠CMV （MCMV）的m157糖蛋白。Ly49H-m157相互作用奠定了C57BL/6小鼠的有效耐药机制（Cmv1）的基础，并作为了解NK细胞如何在体内特异性激活的良好模型，因为类似的受体系统对人类NK细胞起作用。对于分离表达m157的转导细胞和mcmv感染的细胞，我们发现m157以多种亚型表达，在感染的成纤维细胞（高）和巨噬细胞（低）之间的丰度存在显著差异。在细胞表面，m157在mcmv感染的细胞中完全是一个糖基磷脂酰肌醇相关蛋白。通过。在m157的随机和定点突变中，我们发现了独特的残基，这些残基提供了m157的有效细胞表面表达，但无法激活表达ly49h的报告细胞。预计这些m157突变会改变假定的m157与Ly49H界面的构象，该界面依赖于m157的关键α 0螺旋的位置。这些发现支持这种重要NK细胞受体与其病毒配体之间的新型相互作用的新兴模型。
Activated NK cells mediate potent cytolytic and secretory effector functions and are vital components of the early antiviral immune response. NK cell activities are regulated by the assortment of inhibitory receptors that recognize MHC class I ligands expressed on healthy cells and activating receptors that recognize inducible host ligands or ligands that are not well characterized. The activating Ly49H receptor of mouse NK cells is unique in that it specifically recognizes a virally encoded ligand, the m157 glycoprotein of murine CMV (MCMV). The Ly49H-m157 interaction underlies a potent resistance mechanism (Cmv1) in C57BL/6 mice and serves as an excellent model in which to understand how NK cells are specifically activated in vivo, as similar receptor systems are operative for human NK cells. For transduced cells expressing m157 in isolation and for MCMV-infected cells, we show that m157 is expressed in multiple isoforms with marked differences in abundance between infected fibroblasts (high) and macrophages (low). At the cell surface, m157 is exclusively a glycosylphosphatidylinositol-associated protein in MCMV-infected cells. Through. random and site-directed mutagenesis of m157, we identify unique residues that provide for efficient cell surface expression of m157 but fail to activate Ly49H-expressing reporter cells. These m157 mutations are predicted to alter the conformation of a putative m157 interface with Ly49H, one that relies on the position of a critical alpha 0 helix of m157. These findings support an emerging model for a novel interaction between this important NK cell receptor and its viral ligand.