CD4 T cell Immunity to Influenza

甲型流感病毒（fluA）优先在呼吸道中复制，是一种有用的原型， 了解限制呼吸道感染和传播的人类免疫防御机制。 流感A感染每年在全球范围内导致婴儿和老年人的大量发病率和死亡率， 并且由于其易于进行遗传转化的能力， 基因重组可以通过重组DNA技术产生。目前批准的流感疫苗 是三价灭活疫苗（TIV）和Flumist，一种三价减毒活疫苗， 鼻内注射然而，关于疫苗的细胞免疫应答， 自然感染，包括在年龄的极端。CD 4 T细胞是流感病毒的关键成分 通过向B细胞提供CD 154介导的帮助来产生中和性免疫应答 血凝素（HA）抗体，可防止感染和疾病。CD 4 T细胞也 为CD 8 T细胞提供帮助并产生干扰素-γ（IFN-γ）和肿瘤坏死因子-α （TNF-c_），其具有直接抗病毒活性。该项目的主要目标是利用当代 基于单细胞的检测，包括技术项目A-D开发的检测，以确定流感特异性 CD 4 T细胞应答。将分析FluA特异性和HA特异性CD 4 T细胞应答， IFN-γ、TNF-α和CD 154的表达，以及抗原反应性CD 4 T细胞的总频率 基于TCR特异性。重点将是对儿童自然流感感染的反应，以及 在儿童和成人中进行肠胃外或粘膜接种。第二个焦点是定义一个G蛋白连接的 CD 4 T细胞的趋化性受体表型，优先归巢肺， 流感病毒A感染或流感病毒A疫苗接种后血液中这些细胞的频率。这些研究将 为人类CD 4 T细胞对流感病毒感染和疫苗接种的反应提供了实质性的新见解， 包括在年龄的极端，以及它们与其他淋巴细胞效应机制的关系 （项目2-4）。它们也可能指示增强肺宿主防御机制的策略。

Influenza A (fluA) preferentially replicates in the respiratory tract, and is a useful prototype for understanding human immune defense mechanisms that limit respiratory infection and transmission. FluA infection causes annual substantial morbidity and mortality worldwide for infants and the elderly, and is of potential concern as a agent of bioterrorism because of its ability to readily undergo genetic reassortment and be generated by recombinant DNA technology. The current approved FluA vaccines are the trivalent inactivated vaccine (TIV) and Flumist, a trivalent live-attenuated vaccine given intranasally. However, little is known concerning the cellular immune responses to vaccine compared to natural infection, including at the extremes of age. CD4 T cells are key component of the fluA immune response by providing CD 154-mediated help to B cells for the production of neutralizing antibodies to hemagglutinin (HA), which protect against infection and disease. CD4 T cells also provide help to CD8 T cells and produce interferon-gamma (IFN-],) and tumor necrosis-factor-alpha (TNF-c_), which have direct anti-viral activity. The main goal of this project is to use contemporary single-cell based assays, including those developed by Technical Projects A-D, to determine the fluAspecific CD4 T cell response. FluA-specific and HA-specific CD4 T cell responses will be analyzed for expression of IFN-% TNF-c_, and CD154, and the overall frequency of antigen-reactive CD4 T cells based on TCR specificity. The focus will be on the response to natural fluA infection in children, and to parenteral or mucosal vaccination in both children and adults. A second focus is to define a G proteinlinked chemotactic receptor phenotype of CD4 T cells that preferentially home to the lung, and the frequency of these cells in the blood following fluA infection or fluA vaccination. These studies will provide substantial new insights into human CD4 T cell responses to fluA infection and vaccination, including at the extremes of age, and their relationship to other lymphocyte effector mechanisms (Projects 2-4). They may also indicate strategies to augment pulmonary host defense mechanisms.