Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario;
Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario; College of Applied Medical Sciences, Taibah University, Madinah Munawwarah, Saudi Arabia.
Cancer Res. 2014 Jul 15;74(14):3684-94. doi: 10.1158/0008-5472.CAN-13-3021. Epub 2014 May 6.
According to the missing-self hypothesis, natural killer (NK) cells survey for target cells that lack MHC-I molecules. The Ly49 receptor family recognizes loss of MHC-I and is critical for educating NK cells, conferring the ability to eliminate transformed or infected cells. In this study, we evaluated their requirement in innate immune surveillance of cancer cells using genetically manipulated mice with attenuated expression of Ly49 receptors (NKC(KD)) in several models of carcinoma and metastasis. We found that NKC(KD) mice exhibited uncontrolled tumor growth and metastases. Expression of two MHC-I alleles, H-2K(b) and H-2D(b), was decreased in tumors from NKC(KD) mice in support of the likelihood of NK-mediated tumor immunoediting. These tumor cells exhibited directed alterations to their cell surface expression in response to the genetically altered immune environment to evade host recognition. Immunoediting in NKC(KD) mice was restricted to MHC-I molecules, which are ligands for Ly49 receptors, while expression of Rae-1 and Mult1, ligands for another NK cell receptor, NKG2D, were unaffected. Restoring NK cell education in NKC(KD) mice with a transgene for the inhibitory self-MHC-I receptor Ly49I restored suppression of cancer onset and growth. Interestingly, immune surveillance mediated by activating Ly49 receptors remained intact in NKC(KD) mice, as demonstrated by the ability to stimulate the NKG2D receptor with tumor cells or splenocytes expressing Rae-1. Together, our results genetically establish the integral role of Ly49 in NK cell-mediated control of carcinogenesis through MHC-I-dependent missing-self recognition.
根据缺失自我假说，自然杀伤 (NK) 细胞会检测缺乏 MHC-I 分子的靶细胞。Ly49 受体家族识别 MHC-I 的缺失，对于 NK 细胞的教育至关重要，赋予其消除转化或感染细胞的能力。在这项研究中，我们使用几种癌和转移模型中 Ly49 受体表达减弱的基因改造小鼠来评估它们在癌细胞固有免疫监测中的要求。我们发现 NKC(KD) 小鼠表现出不受控制的肿瘤生长和转移。NKC(KD) 小鼠肿瘤中两种 MHC-I 等位基因 H-2K(b) 和 H-2D(b) 的表达降低，支持 NK 介导的肿瘤免疫编辑的可能性。这些肿瘤细胞表现出针对其细胞表面表达的定向改变，以逃避宿主识别，以适应遗传改变的免疫环境。NKC(KD) 小鼠中的免疫编辑仅限于 MHC-I 分子，这些分子是 Ly49 受体的配体，而另一种 NK 细胞受体 NKG2D 的配体 Rae-1 和 Mult1 的表达不受影响。用抑制性自身 MHC-I 受体 Ly49I 的转基因恢复 NKC(KD) 小鼠中的 NK 细胞教育，恢复了对癌症发生和生长的抑制。有趣的是，NKC(KD) 小鼠中的激活 Ly49 受体介导的免疫监视仍然完整，如用表达 Rae-1 的肿瘤细胞或脾细胞刺激 NKG2D 受体的能力所示。总之，我们的结果通过 MHC-I 依赖性缺失自我识别，从遗传学上确立了 Ly49 在 NK 细胞介导的致癌作用控制中的不可或缺作用。
