Heterosubtypic immunity to influenza virus mediated by MHC-E-restricted memory NK cells

季节性流感流行是世界范围内发病率和死亡率的主要原因， 免疫接种已被证明是预防流感最有效的方法，目前的疫苗提供有限的 针对抗原性不同的流感毒株，特别是具有大流行和/或高致病性的流感毒株的保护 潜力因此，与目前获得许可的疫苗相比， 并且抗多种流感病毒是非常需要的。免疫效应细胞的动员 针对保守流感抗原的有效抗病毒活性代表了增强交叉免疫的一种策略。 保护传统上，自然杀伤（NK）细胞被视为先天免疫的非特异性效应细胞。 这些系统在防御病毒感染（包括流感）中起着关键作用。没想到，一年多来， 十年来，表明免疫记忆仅由T和B细胞介导的范例已经被 几项独立的研究清楚地表明，小鼠、非人灵长类动物的亚群 (NHP)并且人NK细胞能够具有适应性免疫功能，包括抗原特异性和回忆 应答我们新的初步数据首次显示，流感特异性NK细胞介导的强效免疫应答， 针对来自血清学上不同菌株的保守流感抗原的应答存在于人类中， 支持HLA-E及其活化配体NKG 2C在抗原特异性NK细胞中作用的机制证据 应答总的来说，这些发现表明，同时提高广度， 流感特异性记忆NK细胞、T细胞和B细胞应答的幅度和交叉反应性可能 显著提高疫苗诱导交叉保护性免疫。然而， 真正抗原特异性NK细胞记忆的建立和维持在很大程度上是不确定的， 流感特异性记忆NK细胞介导的免疫应答在灵长类动物中仍有待确定。本研究 我提出了一个总体假设，即MHC-E限制性记忆NK细胞可以介导 通过三个集中的独立目的针对流感的异亚型保护：（i）表征 人流感特异性记忆NK细胞应答;（ii）评估流感特异性记忆NK细胞- 介导的交叉保护;和（iii）描绘MHC-E限制性NK细胞抗原特异性 对抗流感我们希望这些创新性研究有助于开发通用流感疫苗， 动员流感特异性记忆NK细胞。

Seasonal influenza epidemics are a leading cause of morbidity and mortality worldwide, and while prophylactic immunization has proven the most efficient way to prevent influenza so far, current vaccines provide limited protection against antigenically distinct influenza strains, notably those with pandemic and/or high pathogenic potential. Therefore, innovative approaches to provide longer-lasting protection than currently licensed vaccines and against a wider variety of influenza viruses is highly desirable. Mobilization of immune effector cells with potent antiviral activity against conserved influenza antigens represents one strategy to enhance cross- protection. Classically, Natural Killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections, including influenza. Unexpectedly, for over a decade, paradigms suggesting that immunological memory is exclusively mediated by T and B cells have been challenged by several independent studies clearly demonstrating that subsets of murine, non-human primate (NHP) and human NK cells are capable of adaptive immune functions, including antigen-specificity and recall responses. Our new preliminary data now show for the first time that influenza-specific NK cells mediating potent responses against conserved influenza antigens from serologically distinct strains exist in humans and provide mechanistic evidence supporting a role for HLA-E and its activating ligand NKG2C in antigen-specific NK cell responses. Collectively, these findings suggest that vaccine strategies that concomitantly enhance the breadth, magnitude and cross-reactivity of influenza-specific memory NK cell, T cell and B cell responses might significantly improve vaccine-induced cross-protective immunity. However, mechanisms underlying the establishment and maintenance of true antigen-specific NK cell memory are largely undefined and protection mediated by influenza-specific memory NK cells remain to be determined in primate species. In this study, we propose to address the overarching hypothesis that MHC-E-restricted memory NK cells can mediate heterosubtypic protection against influenza through three focused independent Aims: (i) Characterize human influenza-specific memory NK cell responses; (ii) Assess influenza-specific memory NK cell- mediated cross-protection in macaques; and (iii) Delineate MHC-E-restricted NK cell antigen specificity against influenza. We expect these innovative studies to help develop universal influenza vaccines tailored to mobilize influenza-specific memory NK cells.