Antigen Presentation and T/NK Cell Activation Group (D121), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Germany; Clinical Cooperation Unit "Applied Tumor Immunity" (D120), German Cancer Research Center, Heidelberg, Germany.
Antigen Presentation and T/NK Cell Activation Group (D121), German Cancer Research Center (DKFZ), Heidelberg, Germany; Clinical Cooperation Unit "Applied Tumor Immunity" (D120), German Cancer Research Center, Heidelberg, Germany.
Cell Rep. 2018 Aug 21;24(8):1967-1976.e4. doi: 10.1016/j.celrep.2018.07.069.
Adaptive NK cells are characterized by profound alterations in multiple signaling molecules, transcription factors, and epigenetic modifications compared with canonical NK cells. Although their existence is associated with prior exposure to human cytomegalovirus (HCMV), key questions regarding their regulation and function remain. A large proportion of adaptive NK cells express the activating receptor CD94/NKG2C, binding to human leukocyte antigen E (HLA-E), that presents a limited set of peptides. We show that adaptive NK cells discriminate differences between HLA-E-peptide complexes with exquisite specificity. Prolonged exposure to an environment displaying the HLA-E peptide ligand VMAPRTLFL, derived from the leader sequence of HLA-G, enriched adaptive NK cells with low FcεRγ expression, upregulated CD25 expression, increased proliferative activity, and resulted in elevated antibody-dependent cellular cytotoxicity and IFN-γ responses compared with other HLA-E peptide complexes. Our study demonstrates that recognition of alterations in the HLA-E ligandome via an activating receptor can influence heterologous effector mechanisms and proliferation in adaptive NK cells.
与经典自然杀伤 (NK) 细胞相比，适应性 NK 细胞的多个信号分子、转录因子和表观遗传修饰发生了深刻改变。虽然它们的存在与人类巨细胞病毒 (HCMV) 的先前暴露有关，但关于其调控和功能的关键问题仍然存在。很大一部分适应性 NK 细胞表达激活受体 CD94/NKG2C，该受体与人类白细胞抗原 E (HLA-E) 结合，后者呈递有限的肽段。我们表明，适应性 NK 细胞以极高的特异性区分 HLA-E-肽复合物之间的差异。长时间暴露于 HLA-G 前导序列衍生的 HLA-E 肽配体 VMAPRTLFL 环境中，使具有低 FcεRγ 表达、上调 CD25 表达、增加增殖活性的适应性 NK 细胞富集，与其他 HLA-E 肽复合物相比，导致抗体依赖性细胞毒性和 IFN-γ 反应增强。我们的研究表明，通过激活受体识别 HLA-E 配体组的改变可以影响适应性 NK 细胞中的异源效应机制和增殖。
