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，虽然预防性 到目前为止，免疫接种已被证明是预防流感最有效的方法，目前的疫苗提供的帮助有限 对抗原性不同的流感病毒株的保护，特别是那些具有大流行和/或高致病性的流感病毒株 潜力。因此，提供比目前获得许可的疫苗更持久的保护的创新方法 对抗更多种类的流感病毒是非常可取的。免疫效应细胞的动员 针对保守的流感抗原的有效抗病毒活性代表了一种加强交叉- 保护。自然杀伤细胞(Natural Killer，NK)被认为是天然免疫的非特异性效应细胞 在防御包括流感在内的病毒感染方面发挥关键作用的系统。出乎意料的是，在超过一年的时间里 十年来，表明免疫记忆完全由T和B细胞介导的范式已经被 几项独立研究清楚地表明，小鼠、非人类灵长类动物的亚群 (NHP)和人类NK细胞具有获得性免疫功能，包括抗原特异性和回忆 回应。我们的新的初步数据现在首次显示，流感特异性NK细胞在 针对来自不同血清学毒株的保守流感抗原的反应在人类中存在，并提供 支持人类白细胞抗原E及其激活配体NKG2C在抗原特异性NK细胞中作用的机制证据 回应。总而言之，这些发现表明，同时提高疫苗广度的疫苗策略， 流感特异性记忆NK细胞、T细胞和B细胞反应的大小和交叉反应可能 显著提高疫苗诱导的交叉保护免疫。然而，潜在的机制 真正的抗原特异性NK细胞记忆的建立和维持在很大程度上是未知的和保护的 由流感特异性记忆介导的NK细胞在灵长类物种中仍有待确定。在这项研究中，我们 建议解决MHC-E限制性记忆NK细胞可以介导 通过三个有重点的独立目标提供针对流感的异亚型保护：(I)确定 人类流感特异性记忆NK细胞反应；(Ii)评估流感特异性记忆NK细胞 猕猴体内介导的交叉保护；以及(Iii)MHC-E限制性NK细胞抗原的特异性 预防流感。我们希望这些创新研究有助于开发针对以下方面的通用流感疫苗 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.