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

MHC-E限制性记忆NK细胞介导的流感病毒异亚型免疫

• 批准号: 10390932
• 负责人: Stephanie Jost
• 金额: $ 66.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390932
• 关键词: Address; Adult; Antibodies; Antibody Response; Antigens; Antiviral Agents; B-Lymphocytes; Binding; Cell physiology; Cells; Cessation of life; Data; Development; Disease; Disputes; Effector Cell; Epitopes; Exhibits; Exposure to; Future; Genetic Transcription; Herpesviridae Infections; Human; Immune; Immunity; Immunologic Deficiency Syndromes; Immunologic Memory; Impairment; Infectious Agent; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza vaccination; Innate Immune System; Investigation; Kinetics; Ligands; Lymphocyte; Macaca; Macaca fascicularis; Maintenance; Mediating; Membrane Proteins; Memory; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Neoplasms; Nucleoproteins; Outcome; Pathogenicity; Pathway interactions; Patients; Peptides; Phenotype; Play; Population; Preventative vaccination; Primates; Role; Serology; Severity of illness; Specificity; Specimen; T-Lymphocyte; Testing; Time; Vaccinated; Vaccination; Vaccines; Variant; Viral; Virus; Virus Diseases; cross reactivity; design; immune function; improved; in vivo; influenza epidemic; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; insight; mortality; neutralizing antibody; nonhuman primate; novel vaccines; pandemic disease; prevent; protective efficacy; receptor; response; seasonal influenza; sensitizing antigen; universal influenza vaccine; volunteer

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.

季节性流感流行是全世界发病率和死亡率的主要原因，而预防性流感 免疫接种已被证明是迄今为止预防流感最有效的方法，但目前的疫苗提供的效果有限 预防抗原不同的流感毒株，特别是那些大流行和/或高致病性的流感毒株 潜在的。因此，创新方法可以提供比目前许可的疫苗更持久的保护 并针对更广泛的流感病毒种类是非常理想的。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是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 系统在防御病毒感染（包括流感）方面发挥着关键作用。没想到，一个多 十年来，表明免疫记忆完全由 T 细胞和 B 细胞介导的范式已被提出。 受到几项独立研究的挑战，这些研究清楚地表明鼠类、非人类灵长类动物的子集 (NHP) 和人类 NK 细胞具有适应性免疫功能，包括抗原特异性和记忆能力 回应。我们新的初步数据现在首次表明流感特异性 NK 细胞介导有效的 人类体内存在针对来自血清学不同毒株的保守流感抗原的反应，并提供 支持 HLA-E 及其激活配体 NKG2C 在抗原特异性 NK 细胞中发挥作用的机制证据 回应。总的来说，这些发现表明，同时增强广度的疫苗策略， 流感特异性记忆 NK 细胞、T 细胞和 B 细胞反应的程度和交叉反应性可能 显着提高疫苗诱导的交叉保护性免疫力。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不确定的，并且保护 在灵长类动物中，由流感特异性记忆 NK 细胞介导的机制仍有待确定。在这项研究中，我们 提出解决 MHC-E 限制性记忆 NK 细胞可以介导的总体假设 通过三个重点独立的目标来针对流感提供异亚型保护： (i) 表征 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 - 猕猴介导的交叉保护； (iii) 描绘 MHC-E 限制性 NK 细胞抗原特异性 对抗流感。我们期望这些创新研究有助于开发针对不同人群的通用流感疫苗 调动流感特异性记忆 NK 细胞。