T cell immunity to influenza virus in the aged nasal mucosa

描述（由申请方提供）：拟定研究的目的是阐明流感病毒感染后老年人鼻相关淋巴组织（NALT）中CD8 T细胞应答降低的原因。流感病毒具有很强的传染性，在每年的流行病中平均造成36，000人死亡和226，000人住院。流感是导致死亡的第五大原因，老年人尤其面临风险。随着年龄的增长，免疫应答的进行性下降与老年人疫苗接种的有效性降低有关。此外，新流感病毒株的不断出现减少了免疫接种提供保护的有效期。产生保守病毒组分的T细胞在解决流感病毒感染中至关重要，可以保护免受抗原性不同的挑战，并且它们在老年人中的存在与疫苗效力高度相关。因此，模拟自然感染并诱导T细胞对保守表位的应答的疫苗策略，例如冷适应的减毒活流感病毒（LAIV），将是有利的。然而，由于缺乏研究，市售LAIV“Flumist”未被许可用于老年人。LAIV通过鼻粘膜给药，仅在上呼吸道复制，NALT在诱导免疫应答中起关键作用。关于鼻疫苗接种或感染后的免疫学事件知之甚少。我们在初步研究中表明，实验LAIV免疫老年人的结果在NALT受损的T细胞反应。我们假设NALT的粘膜环境对于流感病毒免疫是至关重要的，但是随着年龄的变化会影响建立适当的CD8 T细胞免疫应答的能力。老年NALT中T细胞数量的减少可能有几个原因：鼻DC诱导CD8 T细胞的能力降低，NALT环境的变化，老年CD4 T细胞对CD8 T细胞的帮助不足，或老年CD8 T细胞迁移到鼻粘膜中的能力变化。我们的目标是阐明在NALT响应LAIV的T细胞效应反应的诱导。我们将确定树突状细胞如何诱导CD8 T细胞以及NALT环境如何影响CD8 T细胞免疫。此外，我们将确定CD8 T细胞进入NALT所需的趋化因子和粘附受体表达谱，所需的CD4 T细胞帮助水平，以及两者如何随年龄而受到影响。拟议的研究对于理解老年人鼻内接种疫苗或自然感染后NALT中如何产生CD8 T细胞免疫的机制至关重要。此外，他们还将为NALT中的“正常”免疫反应提供重要的见解，即（记忆）T细胞如何作为其监视功能的一部分在体内循环。对老年NALT感染后免疫学事件的新发现可能会导致确定改善老年人呼吸道病毒疫苗的策略，老年人是发达国家人口增长最快的部分。 公共卫生相关性：流感病毒每年在老年人中引起重大疾病和死亡，具有反复的季节性流行病和零星的破坏性流行病。这项研究的目的是调查流感病毒免疫后鼻粘膜免疫力发展的基础反应。拟议研究的结果将提供关键信息，可能导致确定改进鼻疫苗的策略。

DESCRIPTION (provided by applicant): The aim of the proposed research is to elucidate the reason(s) for reduced CD8 T cell responses in the nasal- associated lymphoid tissue (NALT) of the aged following influenza virus infection. Influenza viruses are very contagious and cause an average of 36,000 deaths and 226,000 hospitalizations in yearly epidemics. The elderly particularly are at risk with influenza ranking as the fifth leading cause of death. A progressive decline in the immune response with aging is associated with reduced efficacy of vaccination in the elderly. In addition, the continuous emergence of new influenza virus strains reduces the effective period of the protection provided by immunization. T cells generated to conserved viral components are crucial in resolving influenza virus infection, can protect from antigenically disparate challenges, and their presence in the elderly is highly correlated with vaccine efficacy. Thus, vaccine strategies that mimic natural infection and induce T cell responses to conserved epitopes, such as cold-adapted live attenuated influenza virus (LAIV), would be advantageous. However, the commercially available LAIV 'Flumist' is not licensed in the elderly, due to a lack of studies. LAIV is administered via the nasal mucosa and replicates only in the upper respiratory tract, and the NALT could play a crucial role in the induction of immune response. Little is known about the immunological events following either nasal vaccination or infection. We show in preliminary studies that experimental LAIV immunization of the aged results in impaired T cell responses in the NALT. We hypothesize that the mucosal environment of the NALT is crucial for influenza virus immunity, but that changes with age affect the ability to mount an appropriate CD8 T cell immune response. The decrease in T cell number in aged NALT could have several reasons: reduced capability of nasal DCs to induce CD8 T cells, changes in the NALT environment, deficiencies in aged CD4 T cell help to CD8 T cells, or changes in the aged CD8 T cells' capability to migrate into the nasal mucosa. Our goals are to elucidate the induction of the T cell effector response in the NALT in response to LAIV. We will determine how and what dendritic cells induce CD8 T cells and how the NALT environment affects CD8 T cell immunity. Furthermore, we will identify the chemokine and adhesion receptor expression profile required for CD8 T cell entry into the NALT, the level of CD4 T cell help needed, and how both are affected with age. The proposed studies are crucial towards understanding the mechanism(s) of how CD8 T cell immunity is generated in the NALT following intranasal vaccination or natural infection in the aged. In addition, they will provide important insights into the 'normal' immune response in the NALT, i.e. how do (memory) T cells circulate through the body as part of their surveillance function. Novel findings into the immunological events in the aged NALT after infection could lead to the identification of strategies for improvement of vaccines to respiratory viruses for the elderly, which are the fastest growing segment of the population in developed countries. PUBLIC HEALTH RELEVANCE: Influenza viruses cause significant annual illness and death in the elderly with recurrent seasonal epidemics and sporadic devastating pandemics. The goal of the proposed research is to investigate the responses that underlie the development of immunity in the nasal mucosa after influenza virus immunization. Findings from the proposed studies will provide crucial information that could lead to the identification of strategies for improvement of nasal vaccines.