T cell immunity to influenza virus in the aged nasal mucosa

描述(申请人提供)：建议研究的目的是阐明老年人感染流感病毒后鼻腔相关淋巴组织中CD8T细胞反应减少的原因(S)。流感病毒具有很强的传染性，在每年的流行病中平均导致36,000人死亡和226,000人住院。老年人尤其有患流感的风险，流感被列为第五大致死原因。随着年龄的增长，免疫反应逐渐下降，这与老年人接种疫苗的效果降低有关。此外，新的流感病毒株的不断出现缩短了免疫提供的保护的有效期。由保守的病毒成分产生的T细胞对解决流感病毒感染至关重要，可以保护免受抗原性不同的挑战，而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细胞对保守表位的反应的疫苗策略将是有利的，例如冷适应减毒活流感病毒(LAIV)。然而，由于缺乏研究，商业上可用的LAIV‘Flumist’没有在老年人中获得许可。LAIV通过鼻黏膜给药，仅在上呼吸道复制，NALT可能在诱导免疫反应中发挥关键作用。对鼻腔接种疫苗或感染后的免疫学事件知之甚少。我们在初步研究中表明，老年人实验性LAIV免疫导致NALT中T细胞反应受损。我们假设NALT的粘膜环境对流感病毒免疫至关重要，但随着年龄的变化，影响启动适当的CD8 T细胞免疫反应的能力。老年NALT患者T细胞数量减少可能有多种原因：鼻腔树突状细胞诱导CD8T细胞的能力降低，NALT环境的改变，老年CD4T细胞对CD8T细胞的帮助不足，或者老年CD8T细胞迁移到鼻黏膜的能力改变。我们的目标是阐明LAIV在NALT中诱导T细胞效应器反应的机制。我们将确定树突状细胞如何以及什么诱导CD8T细胞，以及NALT环境如何影响CD8T细胞免疫。此外，我们将确定CD8T细胞进入NALT所需的趋化因子和黏附受体的表达谱，所需的CD4T细胞的水平，以及两者如何随年龄的变化而受到影响。建议的研究对于理解鼻腔接种疫苗或老年人自然感染后NALT中CD8T细胞免疫是如何产生的机制(S)至关重要。此外，他们还将对NALT中的“正常”免疫反应提供重要的见解，即(记忆)T细胞如何在体内循环，作为其监视功能的一部分。老年人感染NALT后的免疫学事件的新发现可能会导致确定改进老年人呼吸道病毒疫苗的策略，老年人呼吸道病毒是发达国家人口中增长最快的部分。

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.