Rajagopalan S, Long E O
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852-1727, USA.
J Immunol. 1998 Aug 1;161(3):1299-305.
The lysis of target cells by human NK cells is inhibited by several kinds of receptors with varying specificities for the MHC class I molecules of target cells. The requirements for complete inhibition of NK cytotoxicity appear to be complex and not well defined. The HLA-C-specific members of the killer cell-inhibitory receptor (KIR) family, carrying two Ig domains (KIR2D), are unusual among Ig superfamily members in their ability to bind zinc. A role for the zinc-binding site in KIR-mediated inhibition was demonstrated in this study using a functional reconstitution system in NK cells. Replacement of six histidines by alanine residues in putative zinc binding sites of a KIR2D ablated zinc binding and markedly impaired its inhibitory function, but left intact its ability to bind HLA-C and to transduce a positive signal through an immunoreceptor tyrosine-based activation motif grafted onto its cytoplasmic tail. Thus, zinc modulates specifically the negative signal transmitted by this KIR molecule. Mutation of an exposed amino-terminal zinc-binding motif alone was sufficient to impair the inhibitory function of KIR. The data suggest that complete inhibition of HLA-C-specific NK cells requires a zinc-dependent protein-protein interaction via the amino-terminal end of KIR2D.
人类自然杀伤细胞（NK细胞）对靶细胞的裂解作用受到多种受体的抑制，这些受体对靶细胞的主要组织相容性复合体I类（MHC I类）分子具有不同的特异性。完全抑制NK细胞毒性的条件似乎很复杂，尚未完全明确。杀伤细胞抑制性受体（KIR）家族中针对HLA - C的成员，携带两个免疫球蛋白结构域（KIR2D），在免疫球蛋白超家族成员中，它们结合锌的能力非同寻常。本研究利用NK细胞中的功能重建系统，证明了锌结合位点在KIR介导的抑制作用中的作用。在KIR2D的假定锌结合位点中，将六个组氨酸替换为丙氨酸残基，消除了锌结合能力，并显著损害了其抑制功能，但保留了其结合HLA - C以及通过嫁接到其胞质尾部的基于免疫受体酪氨酸的激活基序转导阳性信号的能力。因此，锌特异性调节该KIR分子传递的负信号。仅使暴露的氨基末端锌结合基序发生突变就足以损害KIR的抑制功能。数据表明，完全抑制针对HLA - C的NK细胞需要通过KIR2D的氨基末端进行锌依赖性蛋白质 - 蛋白质相互作用。
