Braud V M, Allan D S, O'Callaghan C A, Söderström K, D'Andrea A, Ogg G S, Lazetic S, Young N T, Bell J I, Phillips J H, Lanier L L, McMichael A J
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Nature. 1998 Feb 19;391(6669):795-9. doi: 10.1038/35869.
The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
蛋白质HLA - E是一种序列变异性有限的非经典主要组织相容性复合体（MHC）分子。它在细胞表面的表达受源自其他一些MHC I类分子信号序列的肽段结合调控。在此我们报告了HLA - E配体的鉴定。我们构建了四聚体，其中重组HLA - E和β2 - 微球蛋白与一个MHC前导序列肽段重折叠、生物素化，并与藻红蛋白标记的抗生物素蛋白缀合。这种HLA - E四聚体与外周血中的自然杀伤（NK）细胞及一小部分T细胞结合。在转染细胞上，该四聚体与CD94/NKG2A、CD94/NKGK2B和CD94/NKG2C NK细胞受体结合，但不与NK细胞受体的免疫球蛋白家族（KIR）结合。HLA - E的表面表达足以保护靶细胞免受CD94/NKG2A + NK细胞克隆的裂解。已表明一部分HLA I类等位基因可抑制CD94/NKG2A + NK细胞克隆的杀伤作用。只有那些拥有能够上调HLA - E表面表达的前导肽的HLA等位基因才赋予对NK细胞介导的裂解的抗性，这意味着它们的作用是由NK细胞抑制性受体CD94/NKG2A的主要配体HLA - E介导的。
