Robust T-cell Immunity to Influenza in Human Populations

描述（由申请人提供）： 人类对病原体的长期免疫应答是免疫记忆发展的结果。这一过程对健康至关重要，了解记忆是如何形成和进化的对于疫苗开发和疫苗接种的合理方法至关重要。在人类中，记忆T细胞如何在成年期产生或维持，以及T细胞的数量和类型如何随着再次暴露于病原体而变化仍然知之甚少。此外，人类群体如何应对相同的病原体和病原体再次暴露尚未在基本水平上进行调查。在中心补助金，我们调查的记忆细胞毒性，辅助，和γ/δ T细胞流感。这种病原体与反复出现的流行病有关。它来源于大量的禽类病毒库，通过在猪体内重组，可以从禽类转移到人身上。因此，可以操纵病毒来选择更具致病性的类型。在这个中心的补助金，我们将调查的假设，大多数T细胞的记忆是来自一个强大的网络的T细胞时，胸腺产生了大量的幼稚T细胞。使用流感作为我们的模型病原体，我们将研究从血液中研究的记忆T细胞如何与肺中的记忆细胞相关。通过分析多年来一组个体的记忆T细胞库，并将结果与暴露于流感的风险相关联，我们应该详细了解记忆T细胞的复杂网络如何随时间和病原体再暴露而变化。该中心赠款包括四个科学项目，从以下角度探讨上述问题：1）来自血液的I类HLA限制性记忆T细胞反应。2)来自血液的II类HLA限制性记忆T细胞应答。3)支气管肺泡灌洗液中T细胞的反应与血液中T细胞的反应比较。这些研究还将包括分析γ/δ T细胞在反应中的可能作用。4)模拟流感反应谱的性质，并生成流感流行病学的分子描述。 这些研究将得到一些核心的支持，这些核心负责提供通用样本、通用检测和通用试剂。四个技术目标提出了推进剧目分析。

DESCRIPTION (provided by applicant): The long-term human immune response to pathogens results from development of immune memory. This process is vital for health, and understanding how memory is formed and evolves is essential for rational approaches to vaccine development and vaccination. In man, how memory T cells are generated or maintained during the adult years, and how the number and type of T cell changes with re-exposure to pathogen are still poorly understood. Furthermore, how populations of humans respond to the same pathogen and to pathogen re-exposure has not been investigated at a basic level. In the Center Grant we investigate the memory response of cytotoxic, helper, and gamma/delta T cells to influenza. This pathogen is involved in recurring epidemics. It is derived from a large avian pool of viruses that by recombination in pigs can move from birds to man. Thus, the virus could be manipulated to select for more pathogenic types. In this Center Grant we will investigate the hypothesis that most T cell memory is derived from a robust network of T cells that was generated when the thymus was generating a large number of naive T cells. Using influenza as our model pathogen, we will investigate how memory T cells that are studied from blood relate to memory cells in the lung. By analyzing memory T cell repertoires in a cohort of individuals over a number of years, and correlating the results with the risk of exposure to influenza, we should develop a detailed understanding of how the complex network of memory T cells change with time and with pathogen re-exposure. The Center Grant consists of four scientific projects that approach the above issues from the point of view of: 1) Class I HLA-restricted memory T cell responses from blood. 2) Class II HLA-restricted memory T cell responses from blood. 3) Responses of T cells from bronchial alveolar lavages in comparison with those from blood. These studies will also include analyzing the possible role of gamma/delta T cells in the response. 4) Modeling the nature of the responding repertoires and generating a molecular description of the epidemiology of influenza. These studies will be supported by a number of cores that are responsible for providing common samples, common testing and common reagents. Four technical aims are proposed for advancing repertoire analysis.