Regulation of CD8 immunity to intracellular infections

描述(申请人提供)：CD8+T细胞对细胞内病原体如细菌、病毒和原生动物寄生虫的反应是宿主抵抗感染的关键因素。为了产生强大而有效的免疫反应，CD8+T细胞必须整合病原体来源的信号和微环境信号，包括营养和氧气的可获得性。这些信号共同调节效应T细胞的戏剧性扩张以消除病原体和产生免疫记忆所必需的变化。在这些研究中，我们将致力于了解高度保守的HIF通路是如何在CD8+T细胞中发挥作用的。HIF通路在调节新陈代谢和对缺氧/缺氧引起的细胞应激反应中起着核心作用。我们发现，对急性和慢性感染的反应受到HIF活性的不同影响，这表明这一途径没有 在CD8+T细胞反应的背景下进行了研究，控制了效应性和记忆性T细胞功能、分化和免疫病理的多个方面。这些研究的结果将为CD8+T细胞免疫提供新的见解，这一主题在开发慢性感染的治疗策略和疫苗、新出现的感染源和与生物防御相关的微生物方面具有重要意义。此外，我们将研究HIF的药理稳定性与CD8+T细胞功能的临床相关性。HIF是一种在许多疾病背景下靶向的分子。

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.