Regulation of CD8 immunity to intracellular infections

描述（由申请方提供）：CD 8 + T细胞对细胞内病原体（如细菌、病毒和原生动物寄生虫）的应答是宿主抗感染的关键因素。为了产生强大而有效的免疫反应，CD 8 + T细胞必须整合病原体来源的信号和微环境信号，包括营养物质和氧气的可用性。这些信号共同调节效应T细胞急剧扩增所必需的变化，以消除病原体和产生免疫记忆。在这些研究中，我们将致力于了解高度保守的HIF途径如何在CD 8 + T细胞中发挥作用，该途径在调节代谢和对缺氧/缺氧引起的细胞应激的反应中发挥核心作用。我们发现，急性和慢性感染的反应受到HIF活性的不同影响，这表明这一途径， 在CD 8 + T细胞应答的背景下进行了研究，控制效应和记忆T细胞功能的衰减、分化和免疫病理学的多个方面。这些研究的结果将为CD 8 + T细胞免疫提供新的见解，这是一个在慢性感染，新兴感染因子和生物防御相关微生物的治疗策略和疫苗开发中具有重要意义的主题。此外，我们将研究HIF（一种在许多疾病背景下靶向的分子）的药理学稳定与CD 8 + T细胞功能的临床相关性。

DESCRIPTION (provided by applicant): The CD8+ T cel response to intracellular pathogens such as bacteria, viruses, and protozoan parasites is a key element of host resistance to infections. To generate a robust and effective immune response, CD8+ T cells must integrate pathogen-derived and micro-environmental signals, including availability of nutrients and oxygen. Together these signals regulate the changes necessary for the dramatic expansion of effector T cells armed to eliminate pathogens and for the generation of immunological memory. In these studies, we will work to understand how the highly conserved HIF pathway, which plays a central role in regulating metabolism and the response to cellular stress caused by oxygen deficiency/hypoxia, functions in CD8+ T cells. We find that the response to acute and chronic infections are differentially impacted by HIF activity, suggesting that this pathway, which has not been studied in the context of CD8+ T cell responses, controls multiple aspects of the attenuation of effector and memory T cell function, differentiation, and immunopathology. Results from these studies will provide novel insights into the CD8+ T cell immunity, a topic of significance in the development of treatment strategies and vaccines for chronic infections, emerging infectious agents, and microorganisms relevant to biodefense. Furthermore, we will study the clinical relevance of pharmacologic stabilization of HIF, a molecule targeted in numerous disease contexts, to CD8+ T cell function.