Regulation of CD8 immunity to intracellular infections

描述（由申请人提供）：CD8+ T细胞对细胞内病原体（如细菌、病毒和原生动物寄生虫）的反应是宿主抗感染的关键因素。为了产生强大而有效的免疫应答，CD8+ T细胞必须整合病原体来源和微环境信号，包括营养物质和氧气的可用性。这些信号共同调节了用于消灭病原体的效应T细胞的急剧扩张和免疫记忆的产生所必需的变化。在这些研究中，我们将努力了解高度保守的HIF通路如何在CD8+ T细胞中发挥作用，它在调节代谢和对氧缺乏/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，这表明这种途径没有

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.