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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DOI：
10.3389/fimmu.2020.00156
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发表时间：
2020-02-18
影响因子：
7.3
通讯作者：
Peppa, Dimitra
中科院分区：
文献类型：
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作者：
Cubero, Elia Moreno;Ogbe, Ane;Peppa, Dimitra
自然杀伤（NK）细胞在抗病毒防御中发挥着重要作用，其强大的效应功能使它们成为慢性病毒感染免疫治疗干预的关键候选细胞。它们卓越的功能敏捷性是通过一系列种系编码的抑制和激活受体来实现的，确保了自我耐受和可调的全部功能。 NK 细胞多样性是由遗传决定因素和感染/环境因素等因素组合产生的，这些因素共同塑造了 NK 细胞库和功能潜力。最近，HLA-B -21 位的遗传多态性影响了 HLA-E 结合肽的供应以及 HLA-E 被抑制性 NK 细胞受体 NKG2A 识别的可用性，该多态性被证明对健康人巨细胞病毒 (HCMV) 血清阴性白种人个体的 NK 细胞功能有显着影响。在这项研究中，提供 HLA-E 结合肽的-21 蛋氨酸 (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，并且观察到 NKG2A 介导的功能强大 NK 细胞的教育存在偏差。在这里，我们在 36 名人类免疫缺陷病毒 1 型 (HIV-1)/HCMV 混合感染的非洲个体中研究了这种多态性对外周血 NK 细胞表型和功能的影响。 HLA-B-21 位点二态性对 NK 细胞的类似深远影响在这些受试者中并不明显。它们主要表达非洲特有的 HLA-B 和 -C 等位基因，这些等位基因提供了不同的 NKG2A 和 KIR 配体，并且 HIV-1/HCMV 共感染对 NK 细胞分化的显着影响加剧了这些遗传差异。这些因素共同导致 HLA-B -21 多态性与 HLA-E 表面丰度缺乏相关性，并导致具有 -21M HLA-B 等位基因的受试者的 NK 细胞功能优势丧失。相反，我们的数据表明，在 HIV/HCMV 共感染期间，NK 细胞暴露于 HLA-E 配体改变的环境中，会驱动适应性 NKG2C+ NK 细胞扩张，从而影响效应器反应。加大力度了解 NK 细胞在慢性病毒感染期间如何针对自身 HLA 进行功能校准将为开发有针对性的治疗干预措施铺平道路，以克服当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.