Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Division of Biomedical Informatics and Personalized Medicine, Department of Immunology, School of Medicine, University of Colorado Denver, Denver, CO, USA.
Life Sci Alliance. 2019 Nov 13;2(6). doi: 10.26508/lsa.201900434. Print 2019 Dec.
During development, NK cells are "educated" to respond aggressively to cells with low surface expression of HLA class I, a hallmark of malignant and infected cells. The mechanism of education involves interactions between inhibitory killer immunoglobulin-like receptors (KIRs) and specific HLA epitopes, but the details of this process are unknown. Because of the genetic diversity of HLA class I genes, most people have NK cells that are incompletely educated, representing an untapped source of human immunity. We demonstrate how mature peripheral KIR3DL1 human NK cells can be educated in vitro. To accomplish this, we trained NK cells expressing the inhibitory KIR3DL1 receptor by co-culturing them with target cells that expressed its ligand, Bw4HLA-B. After this training, KIR3DL1 NK cells increased their inflammatory and lytic responses toward target cells lacking Bw4HLA-B, as though they had been educated in vivo. By varying the conditions of this basic protocol, we provide mechanistic and translational insights into the process NK cell education.
在发育过程中，NK 细胞会“被教育”对 HLA I 类表面表达低的细胞产生强烈反应，这是恶性和感染细胞的一个标志。教育的机制涉及抑制性杀伤免疫球蛋白样受体 (KIR) 与特定 HLA 表位之间的相互作用，但这一过程的细节尚不清楚。由于 HLA I 类基因的遗传多样性，大多数人具有不完全教育的 NK 细胞，这代表了人类免疫的未开发来源。我们展示了如何在体外对成熟外周 KIR3DL1 人类 NK 细胞进行教育。为了实现这一目标，我们通过与表达其配体 Bw4HLA-B 的靶细胞共培养来训练表达抑制性 KIR3DL1 受体的 NK 细胞。经过这种训练，KIR3DL1 NK 细胞增加了对缺乏 Bw4HLA-B 的靶细胞的炎症和裂解反应，就好像它们在体内受到了教育一样。通过改变这个基本方案的条件，我们为 NK 细胞教育过程提供了机制和转化方面的见解。
