Interrogating adaptive immunity to microbial infection

 描述（由申请人提供）： 慢性传染病（包括丙型肝炎、艾滋病毒和结核病）的死亡率仍然是退伍军人面临的一个主要问题，这使得新疫苗的开发成为生物医学研究的一个重要优先事项。免疫记忆是获得性免疫的一个重要特征，也是疫苗接种策略的一个重要目标。传统的疫苗接种策略在产生针对细菌和病毒的中和抗体方面非常有效。然而，能够产生强大的T细胞记忆的疫苗仍然超出了我们的研究，部分原因是对记忆淋巴细胞命运特化的分子基础的不完全理解。此外，免疫“衰竭”（一种在许多慢性病毒感染期间T细胞变得无效的状态）背后的分子机制仍不完全清楚。因此，从根本上了解记忆淋巴细胞的命运是如何确定的，以及在疲惫状态下发生了什么，是合理设计艾滋病毒、丙型肝炎病毒、疟疾和结核病等传染病疫苗的关键第一步。我们的基本假设是，以前未被重视的分子决定因素控制终端效应和记忆（TCM，TEM和TRM）细胞命运的规范，以及耗尽的CD8+ T细胞状态。我们的目标是使用创新的多学科方法，包括单细胞RNA测序，计算分析和免疫学技术来识别和验证这些决定因素。

 DESCRIPTION (provided by applicant): Mortality from chronic infectious diseases, including Hepatitis C, HIV, and tuberculosis, remains a major problem among Veterans, making the development of new vaccines an important priority of biomedical research. Immunologic memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Traditional vaccination strategies are very effective at generating neutralizing antibodies against bacteria and viruses. However, a vaccine capable of generating robust T cell memory is still beyond our research, due, in part, to an incomplete understanding of the molecular basis for memory lymphocyte fate specification. Moreover, the molecular mechanisms underlying immune `exhaustion,' a state in which T cells are rendered ineffective during many chronic viral infections, remain incompletely understood. Thus, a fundamental understanding of how memory lymphocyte fate is specified, as well as what goes awry in the exhausted state, is a crucial first step in rational vaccine design for infectious diseases such as HIV, HCV, malaria, and tuberculosis. Our underlying hypothesis is that previously unappreciated molecular determinants control the specification of terminal effector and memory (TCM, TEM, and TRM) cell fates as well as the exhausted CD8+ T cell state. Our goal is to identify and validate these determinants using innovative multi-disciplinary approaches that include single-cell RNA sequencing, computational analyses, and immunological techniques.