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鼠源和人源抗体结合 HLA-E-肽复合物并增强 NK 细胞的细胞毒性。

Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity.

机构信息

Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, 27710, USA.

Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.

出版信息

Commun Biol. 2022 Mar 28;5(1):271. doi: 10.1038/s42003-022-03183-5.

DOI:10.1038/s42003-022-03183-5
PMID:35347236
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8960791/
Abstract

The non-classical class Ib molecule human leukocyte antigen E (HLA-E) has limited polymorphism and can bind HLA class Ia leader peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell receptors NKG2A-C/CD94 and regulate NK cell-mediated cytotoxicity. Here we report the isolation of 3H4, a murine HLA-E-VL9-specific IgM antibody that enhances killing of HLA-E-VL9-expressing cells by an NKG2A NK cell line. Structural analysis reveal that 3H4 acts by preventing CD94/NKG2A docking on HLA-E-VL9. Upon in vitro maturation, an affinity-optimized IgG form of 3H4 showes enhanced NK killing of HLA-E-VL9-expressing cells. HLA-E-VL9-specific IgM antibodies similar in function to 3H4 are also isolated from naïve B cells of cytomegalovirus (CMV)-negative, healthy humans. Thus, HLA-E-VL9-targeting mouse and human antibodies isolated from the naïve B cell antibody pool have the capacity to enhance NK cell cytotoxicity.

摘要

非经典 Ib 类分子人类白细胞抗原 E（HLA-E）具有有限的多态性，可结合 HLA Ia 类前导肽（VL9）。HLA-E-VL9 复合物与自然杀伤（NK）细胞受体 NKG2A-C/CD94 相互作用，并调节 NK 细胞介导的细胞毒性。在这里，我们报告了分离出的 3H4，这是一种针对 HLA-E-VL9 的鼠源 HLA-E-VL9 特异性 IgM 抗体，可增强 NKG2A NK 细胞系对 HLA-E-VL9 表达细胞的杀伤作用。结构分析表明，3H4 通过阻止 CD94/NKG2A 与 HLA-E-VL9 的对接来发挥作用。在体外成熟过程中，经过亲和力优化的 3H4 IgG 形式显示出增强的对 HLA-E-VL9 表达细胞的 NK 杀伤作用。与 3H4 具有相似功能的 HLA-E-VL9 特异性 IgM 抗体也可从巨细胞病毒（CMV）阴性的健康人类的初始 B 细胞中分离出来。因此，从初始 B 细胞抗体库中分离出的 HLA-E-VL9 靶向的鼠源和人源抗体具有增强 NK 细胞细胞毒性的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/3e5e010c8dc2/42003_2022_3183_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/614ea272ee69/42003_2022_3183_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/937be1f7a399/42003_2022_3183_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/b1565bdcf42d/42003_2022_3183_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/457f84322f52/42003_2022_3183_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/3e5e010c8dc2/42003_2022_3183_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/614ea272ee69/42003_2022_3183_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/937be1f7a399/42003_2022_3183_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/b1565bdcf42d/42003_2022_3183_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/457f84322f52/42003_2022_3183_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/651d/8960791/3e5e010c8dc2/42003_2022_3183_Fig5_HTML.jpg

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