Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo
Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo
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DOI：
10.1073/pnas.0901653106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Ugolini, Sophie
中科院分区：
文献类型：
--
作者：
Sola, Caroline;Andre, Pascale;Ugolini, Sophie
自然杀伤细胞（NK）是先天免疫系统的淋巴细胞，能够识别和杀死缺乏自身mhc I类分子的肿瘤。这种“自我缺失”的识别是由MHC i类特异性抑制性NK细胞受体（包括人类的杀伤细胞igg样受体（KIR）和小鼠的Ly49分子）缺乏参与介导的。利用单克隆抗体（mAb）阻断NK细胞抑制受体是一种很有前途的针对MHC I类癌细胞的免疫治疗策略。然而，MHC I类分子与其抑制受体之间的相互作用也是获得NK细胞功能能力所必需的，这一过程被称为“教育”。此外，抑制受体还参与NK细胞的自我耐受。在这里，我们开发了一种临床前小鼠模型，其中所有NK细胞都通过与HLA-Cw3配体结合的单一转基因抑制受体人类KIR2DL3进行教育。这种方法揭示了NK细胞可以被重新编程来控制小鼠体内同源性肿瘤的发展。此外，体内抗kir单抗治疗可诱导杀死HLA（+）靶细胞而不破坏自身耐受性。最后，长期输注抗kir单抗既不破坏NK细胞教育，也不破坏肿瘤细胞识别。因此，这些结果强烈支持在癌症患者中使用抑制性受体阻断。
Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I+ cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.