Molecular and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
J Immunol. 2011 May 15;186(10):5538-42. doi: 10.4049/jimmunol.1002254. Epub 2011 Apr 4.
Although the importance of membrane microdomains in receptor-mediated activation of lymphocytes has been established, much less is known about the role of receptor ligand distribution on APC and target cells. Detergent-resistant membrane domains, into which GPI-linked proteins partition, are enriched in cholesterol and glycosphingolipids. ULBP1 is a GPI-linked ligand for natural cytotoxicity receptor NKG2D. To investigate how ULBP1 distribution on target cells affects NKG2D-dependent NK cell activation, we fused the extracellular domain of ULBP1 to the transmembrane domain of CD45. Introduction of this transmembrane domain eliminated the association of ULBP1 with the detergent-resistant membrane fraction and caused a significant reduction of cytotoxicity and degranulation by NK cells. Clustering and lateral diffusion of ULBP1 was not affected by changes in the membrane anchor. These results show that the partitioning of receptor ligands in discrete membrane domains of target cells is an important determinant of NK cell activation.
虽然已经确定了膜微区在淋巴细胞受体介导的激活中的重要性，但对于受体配体在 APC 和靶细胞上的分布的作用知之甚少。与 GPI 连接的蛋白分隔的去污剂抗性膜域富含胆固醇和糖脂。ULBP1 是天然细胞毒性受体 NKG2D 的 GPI 连接配体。为了研究靶细胞上 ULBP1 的分布如何影响 NKG2D 依赖性 NK 细胞的激活，我们将 ULBP1 的细胞外结构域融合到 CD45 的跨膜结构域上。引入这个跨膜结构域消除了 ULBP1 与去污剂抗性膜部分的关联，并导致 NK 细胞的细胞毒性和脱颗粒作用显著降低。ULBP1 的聚类和侧向扩散不受膜锚定变化的影响。这些结果表明，受体配体在靶细胞离散膜域中的分配是 NK 细胞激活的重要决定因素。
