Subordinate effect of -21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin
Subordinate effect of -21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin
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-21M HLA-B 二态性对非洲血统 HIV-1 感染者 NK 细胞库多样性和功能的从属影响
DOI：
10.1101/786392
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Cubero E
中科院分区：
文献类型：
--
作者：
Cubero E
自然杀伤（NK）细胞在抗病毒防御中发挥重要作用，其有效的效应器功能使其成为慢性病毒感染免疫干预的关键候选者。它们卓越的功能敏捷性是通过一系列广泛的种系编码的抑制性和激活性受体来实现的，这些受体确保了自我耐受和可调的库。NK细胞多样性是由多种因素组合产生的，包括遗传决定因素和感染/环境因素，它们共同塑造了NK细胞库和功能潜力。最近，在HLA-B的位置-21处的遗传多态性（其影响HLA-E结合肽的供应和HLA-E被抑制性NK细胞受体NKG 2A识别的可用性）被证明对健康人巨细胞病毒（HCMV）血清阴性高加索个体中的NK细胞功能具有显著影响。在这项研究中，提供HLA-E结合肽的~ 21甲硫氨酸（M）表达等位基因在很大程度上是抑制性杀伤免疫球蛋白样受体（KIR）的不良配体，观察到对NKG 2A介导的功能有效NK细胞的教育的偏倚。在这里，我们研究了这种多态性对外周血NK细胞的表型和功能能力的影响，在一个队列的36名非洲人免疫缺陷病毒1型（HIV-1）/HCMV合并感染的个人。在这些受试者中，HLA-B的-21位二态性对NK细胞的类似深刻影响并不明显。它们主要表达非洲特异性HLA-B和-C等位基因，这些等位基因提供了不同的NKG 2A和KIR配体供应，这些遗传差异因HIV-1/HCMV共感染对NK细胞分化的显著影响而加剧。总之，这些因素导致HLA-B-21多态性与HLA-E表面丰度缺乏相关性，以及具有-21M HLA-B等位基因的受试者中NK细胞功能优势的丧失。相反，我们的数据表明，在HIV/HCMV共感染过程中，NK细胞暴露于显示改变的HLA-E配体的环境中会驱动适应性NKG 2C + NK细胞扩增，影响效应子应答。进一步努力了解NK细胞在慢性病毒感染期间如何在功能上校准到自身HLA，将为开发有针对性的治疗干预措施铺平道路，以克服目前增强基于免疫的抗病毒控制的障碍。
Natural Killer (NK) cells play an important role in antiviral defense and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline-encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position -21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, -21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of peripheral blood NK cells in a cohort of 36 African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position -21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and -C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV-1/HCMV co-infection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B -21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with -21M HLA-B alleles. Instead, our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.