Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis.
Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis.
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DOI：
10.1084/jem.187.5.813
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发表时间：
1998-03-02
期刊：
影响因子：
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通讯作者：
Brooks AG
中科院分区：
文献类型：
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作者：
Borrego F;Ulbrecht M;Weiss EH;Coligan JE;Brooks AG
人类组织相容性白细胞抗原（HLA）-E是一种非经典的HLA I类分子，其基因在大多数组织中都有转录。最近有报道称，该分子可结合源自HLA I类蛋白信号序列的肽段；然而，HLA - E的功能尚未被描述。我们发现自然杀伤（NK）细胞能够识别在细胞表面表达HLA - E分子的靶细胞，并且这种相互作用会抑制裂解过程。此外，HLA - E的识别主要是通过CD94/NKG2 - A异二聚体介导的，因为特异性针对CD94的单克隆抗体（mAbs），而非特异性针对杀伤细胞抑制性受体（KIR）的mAbs，能够阻断HLA - E对靶细胞的保护作用。通过与来自多种HLA I类分子信号序列的第3 - 11位残基对应的合成肽段一起孵育，细胞表面的HLA - E可增加；然而，只有在第2位含有甲硫氨酸（Met）的肽段能够赋予对NK介导的裂解的抗性，而在第2位为苏氨酸（Thr）的肽段则没有这种作用。有趣的是，先前与CD94/NKG2识别相关的HLA I类分子在信号序列的第4位残基（HLA - E结合肽的第2位）都为甲硫氨酸，而据报道那些不与CD94/NKG2相互作用的分子在该位置为苏氨酸。因此，这些数据表明了HLA - E的一种功能，并为CD94/NKG2与HLA I类分子明显的广泛反应性提供了另一种解释；即CD94/NKG2与HLA - E结合，而HLA - E是与源自“保护性”HLA I类等位基因的信号序列肽段形成复合物，而非直接与经典的HLA I类蛋白相互作用。
Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical HLA class I molecule, the gene for which is transcribed in most tissues. It has recently been reported that this molecule binds peptides derived from the signal sequence of HLA class I proteins; however, no function for HLA-E has yet been described. We show that natural killer (NK) cells can recognize target cells expressing HLA-E molecules on the cell surface and this interaction results in inhibition of the lytic process. Furthermore, HLA-E recognition is mediated primarily through the CD94/NKG2-A heterodimer, as CD94-specific, but not killer cell inhibitory receptor (KIR)–specific mAbs block HLA-E–mediated protection of target cells. Cell surface HLA-E could be increased by incubation with synthetic peptides corresponding to residues 3–11 from the signal sequences of a number of HLA class I molecules; however, only peptides which contained a Met at position 2 were capable of conferring resistance to NK-mediated lysis, whereas those having Thr at position 2 had no effect. Interestingly, HLA class I molecules previously correlated with CD94/NKG2 recognition all have Met at residue 4 of the signal sequence (position 2 of the HLA-E binding peptide), whereas those which have been reported not to interact with CD94/NKG2 have Thr at this position. Thus, these data show a function for HLA-E and suggest an alternative explanation for the apparent broad reactivity of CD94/NKG2 with HLA class I molecules; that CD94/NKG2 interacts with HLA-E complexed with signal sequence peptides derived from “protective” HLA class I alleles rather than directly interacting with classical HLA class I proteins.