The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand
The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand
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DOI：
10.1073/pnas.93.21.11792
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发表时间：
1996-10-15
影响因子：
11.1
通讯作者：
Yokoyama, WM
中科院分区：
文献类型：
--
作者：
Orihuela, M;Margulies, DH;Yokoyama, WM
自然杀伤细胞（NK）被主要组织相容性复合体（MHC） I类分子抑制，无法杀死细胞目标。在小鼠中，这可以通过Ly-49A NK细胞受体介导，该受体特异性结合H-2D(d) MHC I类分子，然后抑制NK细胞活性。先前的实验表明，Ly-49A识别MHC I类的α 1/ α 2结构域，并且没有特异性的MHC结合肽参与其中。我们在这里证明，丙氨酸取代肽，只有最小的锚定基序，稳定H-2D(d)表达，并提供抵抗h - 2dd转染，与加工（TAP）缺陷细胞相关的转运体被Ly-49A(+) NK细胞裂解。肽诱导的耐药仅被结合H-2D构象决定因子的单克隆抗体阻断(d)。此外，外源性β(2)-微球蛋白稳定“空”H-2D(d)重链并没有产生耐药性。与MHC i类限制性T细胞对MHC分子显示的肽具有特异性的数据相反，这些数据表明NK细胞对肽诱导的构象决定因素具有特异性，独立于特定肽。NK细胞和T细胞之间的这种基本区别进一步表明NK细胞仅对MBC I类构象或表达的全局变化敏感，而不是对特定病原体编码的肽敏感。这与“缺失自我”假说是一致的，该假说认为NK细胞会检查组织中MHC I类的正常表达。
Natural killer (NK) cells are inhibited from killing cellular targets by major histocompatibility complex (MHC) class I molecules. In the mouse, this can be mediated by the Ly-49A NK cell receptor that specifically binds the H-2D(d) MHC class I molecule, then inhibits NK cell activity. Previous experiments have indicated that Ly-49A recognizes the alpha 1/alpha 2 domains of MHC class I and that no specific MHC-bound peptide appeared to be involved. We demonstrate here that alanine-substituted peptides, having only the minimal anchor motifs, stabilized H-2D(d) expression and provided resistance to H-2Dd-transfected, transporter associated with processing (TAP)-deficient cells from lysis by Ly-49A(+) NK cells. Peptide-induced resistance was blocked only by an mAb that binds a conformational determinant on H-2D(d). Moreover, stabilization of ''empty'' H-2D(d) heavy chains by exogenous beta(2)-microglobulin did not confer resistance. In contrast to data for MHC class I-restricted T cells that are specific for peptides displayed by MHC molecules, these data indicate that NK cells are specific for a peptide-induced conformational determinant, independent of specific peptide. This fundamental distinction between NK cells and T cells further implies that NK cells are sensitive only to global changes in MBC class I conformation or expression, rather than to specific pathogen-encoded peptides. This is consistent with the ''missing self'' hypothesis, which postulates that NK cells survey tissues for normal expression of MHC class I.