Rheumatology Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Immunol. 2011 Apr 1;186(7):3911-7. doi: 10.4049/jimmunol.1004168. Epub 2011 Feb 18.
NK cells become functionally competent to be triggered by their activation receptors through the interaction of NK cell inhibitory receptors with their cognate self-MHC ligands, an MHC-dependent educational process termed "licensing." For example, Ly49A(+) NK cells become licensed by the interaction of the Ly49A inhibitory receptor with its MHC class I ligand, H2D(d), whereas Ly49C(+) NK cells are licensed by H2K(b). Structural studies indicate that the Ly49A inhibitory receptor may interact with two sites, termed site 1 and site 2, on its H2D(d) ligand. Site 2 encompasses the α1/α2/α3 domains of the H2D(d) H chain and β(2)-microglobulin (β2m) and is the functional binding site for Ly49A in effector inhibition. Ly49C functionally interacts with a similar site in H2K(b). However, it is currently unknown whether this same site is involved in Ly49A- or Ly49C-dependent licensing. In this study, we produced transgenic C57BL/6 mice expressing wild-type or site 2 mutant H2D(d) molecules and studied whether Ly49A(+) NK cells are licensed. We also investigated Ly49A- and Ly49C-dependent NK licensing in murine β2m-deficient mice that are transgenic for human β2m, which has species-specific amino acid substitutions in β2m. Our data from these transgenic mice indicate that site 2 on self-MHC is critical for Ly49A- and Ly49C-dependent NK cell licensing. Thus, NK cell licensing through Ly49 involves specific interactions with its MHC ligand that are similar to those involved in effector inhibition.
NK 细胞通过其抑制性受体与自身 MHC 配体的相互作用而获得被激活受体触发的功能能力，这是一个 MHC 依赖性的教育过程，称为“许可”。例如，Ly49A(+)NK 细胞通过 Ly49A 抑制性受体与 MHC I 类配体 H2D(d)的相互作用而被许可，而 Ly49C(+)NK 细胞则由 H2K(b)许可。结构研究表明，Ly49A 抑制性受体可能与自身 H2D(d)配体上的两个位点相互作用，称为位点 1 和位点 2。位点 2 包含 H2D(d)H 链的α1/α2/α3 结构域和β2-微球蛋白 (β2m)，是 Ly49A 在效应器抑制中的功能结合位点。Ly49C 与 H2K(b)中的类似位点在功能上相互作用。然而，目前尚不清楚该相同位点是否参与 Ly49A 或 Ly49C 依赖性的许可。在这项研究中，我们产生了表达野生型或位点 2 突变体 H2D(d)分子的转基因 C57BL/6 小鼠，并研究了 Ly49A(+)NK 细胞是否被许可。我们还研究了在转人β2m 的小鼠中 Ly49A 和 Ly49C 依赖性 NK 许可，该小鼠β2m 缺乏，并且具有β2m 中特定物种氨基酸取代。我们从这些转基因小鼠的数据表明，自身 MHC 上的位点 2 对于 Ly49A 和 Ly49C 依赖性 NK 细胞许可至关重要。因此，通过 Ly49 的 NK 细胞许可涉及与 MHC 配体的特异性相互作用，与效应器抑制中涉及的相互作用相似。
