Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D
Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D
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DOI：
10.4049/jimmunol.175.8.5463
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发表时间：
2005-10-15
影响因子：
4.4
通讯作者：
Seebach, JD
中科院分区：
文献类型：
--
作者：
Forte, P;Lilienfeld, BG;Seebach, JD
猪到人的异种移植已被提出作为缓解人体器官移植短缺的一种手段，但细胞排斥仍然是异种移植成功存活的障碍。NK细胞与异种移植排斥反应有关，并通过激活和抑制受体识别潜在靶细胞上的配体而受到严格调节。本研究的目的是分析激活NK受体包括NKp30、NKp44、NKp46和NKG2D在人异种NK细胞毒性猪内皮细胞（pEC）中的作用。使用新分离的、il -2激活的多克隆NK细胞群和NK克隆组进行Cr-51释放和Ab阻断试验。新分离的NK细胞是NKp44阴性的，并且仅以nkg2d依赖的方式裂解pEC。相反，激活的人NK细胞介导的pEC裂解依赖于NKp44和NKG2D，因为pEC的完全保护只能通过同时阻断这些激活的NK受体来实现。通过NK克隆，我们发现抗猪NK细胞毒性与NKp44表达水平高度相关。其他触发受体如NKp30和NKp46不参与异种NK细胞毒性。最后，在异种反应性Ab存在的情况下，由人NK细胞介导的Ab依赖性细胞介导的pEC细胞毒性不受NK受体激活阻断的影响。综上所述，旨在抑制NKp44和NKG2D在人NK细胞上的相互作用以及迄今为止未知的pEC配体的策略可能会阻止NK对异种移植物的直接反应，但不会阻止异种抗体依赖性细胞介导的细胞毒性。
Pig-to-human xenotransplantation has been proposed as a means to alleviate the shortage of human organs for transplantation, but cellular rejection remains a hurdle for successful xenograft survival. NK cells have been implicated in xenograft rejection and are tightly regulated by activating and inhibitory receptors recognizing ligands on potential target cells. The aim of the present study was to analyze the role of activating NK receptors including NKp30, NKp44, NKp46, and NKG2D in human xenogeneic NK cytotoxicity against porcine endothelial cells (pEC). Cr-51 release and Ab blocking assays were performed using freshly isolated, IL-2-activated polyclonal NK cell populations as well as a panel of NK clones. Freshly isolated NK cells are NKp44 negative and lysed pEC exclusively in an NKG2D-dependent fashion. In contrast', the lysis of pEC mediated by activated human NK cells depended on both NKp44 and NKG2D, since a complete protection of pEC was achieved only by simultaneous blocking of these activating NK receptors. Using a panel of NK clones, a highly significant correlation between anti-pig NK cytotoxicity and NKp44 expression levels was revealed. Other triggering receptors such as NKp30 and NKp46 were not involved in xenogeneic NK cytotoxicity. Finally, Ab-dependent cell-mediated cytotoxicity of pEC mediated by, human NK cells in the presence of xenoreactive Ab was not affected by blocking of activating NK receptors. In conclusion, strategies aimed to inhibit interactions between NKp44 and NKG2D on human NK cells and so far unknown ligands on pEC may prevent direct NK responses against xenografts but not xenogeneic Ab-dependent cell-mediated cytotoxicity.