美国麻省理工学院和哈佛大学Mary Carrington团队近期取得重要工作进展，他们研究发现HLA I类信号肽多态性决定了CD94/NKG2–HLA-E介导的效应细胞反应调节水平。相关研究成果2023年6月1日在线发表于《自然—免疫学》杂志上。

据介绍，人类白细胞抗原（HLA）-E结合来源于HLA-A、HLA-B、HLA-C和HLA-G信号肽（SP）的表位，并作为在自然杀伤细胞和T细胞亚群上表达的CD94/NKG2A和CD94/NKK2C受体的配体。

研究人员发现，在16种常见的经典HLA I类SP变体中，只有6种可以被有效处理以产生能够使CD94/NKG2结合的表位，称之为“功能性SP”。被称为HLA-B/−21M的单一功能性HLA-B SP诱导了HLA-E的高表达，但赋予了最低的受体识别。因此，HLA-B/−21M SP与其他SP竞争提供HLA-E的表位，并降低CD94/NKG2A对靶细胞的总体识别，这需要重新评估以前涉及HLA-B/–21M的疾病模型。遗传群体数据表明，人类功能性SP的频率与相应的巨细胞病毒模拟物之间呈正相关，这表明病毒可以从宿主反应中逃逸。

总之，这一研究所述的系统、定量方法将有助于开发预测算法，以准确测量CD94/NKG2–HLA-E相互作用对疾病耐药性/易感性的影响。

附：英文原文

Title: HLA class I signal peptide polymorphism determines the level of CD94/NKG2–HLA-E-mediated regulation of effector cell responses

Author: Lin, Zhansong, Bashirova, Arman A., Viard, Mathias, Garner, Lee, Quastel, Max, Beiersdorfer, Maya, Kasprzak, Wojciech K., Akdag, Marjan, Yuki, Yuko, Ojeda, Pedro, Das, Sudipto, Andresson, Thorkell, Naranbhai, Vivek, Horowitz, Amir, McMichael, Andrew J., Hoelzemer, Angelique, Gillespie, Geraldine M., Garcia-Beltran, Wilfredo F., Carrington, Mary

Issue&Volume: 2023-06-01

Abstract: Human leukocyte antigen (HLA)-E binds epitopes derived from HLA-A, HLA-B, HLA-C and HLA-G signal peptides (SPs) and serves as a ligand for CD94/NKG2A and CD94/NKG2C receptors expressed on natural killer and T cell subsets. We show that among 16 common classical HLA class I SP variants, only 6 can be efficiently processed to generate epitopes that enable CD94/NKG2 engagement, which we term ‘functional SPs’. The single functional HLA-B SP, known as HLA-B/21M, induced high HLA-E expression, but conferred the lowest receptor recognition. Consequently, HLA-B/21M SP competes with other SPs for providing epitope to HLA-E and reduces overall recognition of target cells by CD94/NKG2A, calling for reassessment of previous disease models involving HLA-B/21M. Genetic population data indicate a positive correlation between frequencies of functional SPs in humans and corresponding cytomegalovirus mimics, suggesting a means for viral escape from host responses. The systematic, quantitative approach described herein will facilitate development of prediction algorithms for accurately measuring the impact of CD94/NKG2–HLA-E interactions in disease resistance/susceptibility.

DOI: 10.1038/s41590-023-01523-z

Source: https://www.nature.com/articles/s41590-023-01523-z