Song Hyunkeun, Kim JeongKi, Cosman David, Choi Inpyo
Department of Anatomy, Inje University College of Medicine, Pusan 614-735, Republic of Korea.
Cell Immunol. 2006 Jan;239(1):22-30. doi: 10.1016/j.cellimm.2006.03.002. Epub 2006 Apr 21.
NKG2D is an activating receptor that is expressed on most natural killer (NK) cells and CD8(+) T cells. MHC class I-related chain A(MICA) and UL16-binding protein (ULBP) 1, 2, and 3 are well-known ligands for NKG2D. Human gastric cancer cell lines, SNU216 and SNU638 cells which expressed UL16-binding protein (ULBP) were susceptible to NK cells in a NKG2D-dependent manner. However, SNU484 and SNU620 cells which had no ULBP on their surface were resistant to NK cells. ULBP 1, 2, and 3 are glycosylphosphatidylinositol (GPI)-anchored proteins which are sensitive to phosphatidylinositol-specific phospholipase C (PI-PLC). When SNU620 cells were treated with U73122, an inhibitor of PI-PLC, the surface expression of ULBP was elevated with increased NK susceptibility. Pre-incubating NK cells with culture supernatants of SNU620 or SNU638 cells, which contained soluble ULBP protein, reduced NK cell activity by decreasing surface expression of NKG2D in NK cells. Furthermore, recombinant ULBP-Fc induced the down-regulation of NKG2D expression in NK cells. Taken together, down-regulation of NKG2D by soluble ULBP provides a potential mechanism by which gastric cancer cells escape NKG2D-mediated attack by the immune cells.
NKG2D是一种激活受体，在大多数自然杀伤（NK）细胞和CD8(+) T细胞上表达。MHC I类相关链A（MICA）和UL16结合蛋白（ULBP）1、2和3是NKG2D的著名配体。表达UL16结合蛋白（ULBP）的人胃癌细胞系SNU216和SNU638细胞以NKG2D依赖的方式对NK细胞敏感。然而，表面没有ULBP的SNU484和SNU620细胞对NK细胞具有抗性。ULBP 1、2和3是糖基磷脂酰肌醇（GPI）锚定蛋白，对磷脂酰肌醇特异性磷脂酶C（PI-PLC）敏感。当用PI-PLC抑制剂U73122处理SNU620细胞时，ULBP的表面表达升高，NK敏感性增加。用含有可溶性ULBP蛋白的SNU620或SNU638细胞培养上清液预孵育NK细胞，通过降低NK细胞中NKG2D的表面表达来降低NK细胞活性。此外，重组ULBP-Fc诱导NK细胞中NKG2D表达的下调。综上所述，可溶性ULBP对NKG2D的下调提供了一种潜在机制，通过该机制胃癌细胞能够逃避免疫细胞介导的NKG2D攻击。
