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反应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演变的，对于合理地开发疫苗和接种疫苗至关重要。在人类中，记忆T细胞是如何在成年期间产生或维持的，以及T细胞的数量和类型如何随着再次接触病原体而变化，仍然知之甚少。此外，人类群体对同一病原体和病原体再次暴露的反应还没有在基本水平上进行调查。在中心赠款中，我们研究了细胞毒T细胞、辅助性T细胞和伽马/德尔塔T细胞对流感的记忆反应。这种病原体与反复流行有关。它来自一个庞大的禽类病毒库，通过在猪体内的重组，这些病毒库可以从鸟类传播给人类。因此，病毒可以被操纵来选择更多的致病类型。在这个中心格兰特，我们将调查假设，大多数T细胞记忆来自一个强大的T细胞网络产生时，胸腺产生大量的幼稚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。通过分析一组人多年来的记忆T细胞谱系，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着时间和病原体的再次暴露而变化。中心拨款由四个科学项目组成，从以下角度探讨上述问题：1)血液中I类人类白细胞抗原限制的记忆T细胞反应。2)血液中人类白细胞抗原II类限制性记忆T细胞反应。3)从支气管肺泡灌洗液中提取的T细胞与从血液中提取的T细胞的反应性比较。这些研究还将包括分析伽马/德尔塔T细胞在反应中的可能作用。4)对响应曲目的性质进行建模，并生成流感流行病学的分子描述。 这些研究将得到负责提供共同样品、共同检测和共同试剂的若干核心的支持。提出了推进曲目分析的四个技术目标。

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.