Molfetta Rosa, Quatrini Linda, Santoni Angela, Paolini Rossella
Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy.
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France.
Int J Mol Sci. 2017 Aug 2;18(8):1677. doi: 10.3390/ijms18081677.
Natural-killer receptor group 2, member D (NKG2D) is a well characterized natural killer (NK) cell activating receptor that recognizes several ligands poorly expressed on healthy cells but up-regulated upon stressing stimuli in the context of cancer or viral infection. Although NKG2D ligands represent danger signals that render target cells more susceptible to NK cell lysis, accumulating evidence demonstrates that persistent exposure to ligand-expressing cells causes the decrease of NKG2D surface expression leading to a functional impairment of NKG2D-dependent NK cell functions. Upon ligand binding, NKG2D is internalized from the plasma membrane and sorted to lysosomes for degradation. However, receptor endocytosis is not only a mechanism of receptor clearance from the cell surface, but is also required for the proper activation of signalling events leading to the functional program of NK cells. This review is aimed at providing a summary of current literature relevant to the molecular mechanisms leading to NKG2D down-modulation with particular emphasis given to the role of NKG2D endocytosis in both receptor degradation and signal propagation. Examples of chronic ligand-induced down-regulation of NK cell activating receptors other than NKG2D, including natural cytotoxicity receptors (NCRs), DNAX accessory molecule-1 (DNAM1) and CD16, will be also discussed.
自然杀伤受体2族D成员（NKG2D）是一种特征明确的自然杀伤（NK）细胞激活受体，它能识别几种在健康细胞上低表达但在癌症或病毒感染等应激刺激下上调的配体。尽管NKG2D配体代表着使靶细胞更易被NK细胞裂解的危险信号，但越来越多的证据表明，持续暴露于表达配体的细胞会导致NKG2D表面表达下降，从而导致NKG2D依赖的NK细胞功能受损。配体结合后，NKG2D从质膜内化并分选到溶酶体进行降解。然而，受体胞吞作用不仅是受体从细胞表面清除的一种机制，也是导致NK细胞功能程序的信号事件正确激活所必需的。本综述旨在总结当前与导致NKG2D下调的分子机制相关的文献，特别强调NKG2D胞吞作用在受体降解和信号传播中的作用。还将讨论除NKG2D之外的慢性配体诱导的NK细胞激活受体下调的例子，包括自然细胞毒性受体（NCR）、DNAX辅助分子-1（DNAM1）和CD16。
