Resistance to T cell exhaustion

抵抗 T 细胞耗竭

• 批准号: 10684084
• 负责人: Allan J Zajac
• 金额: $ 53.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684084
• 关键词: Acceleration; Adopted; Adoptive Transfer; Antiviral Response; Attenuated; Biochemical; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Chronic Phase; Containment; Cytokine Signaling; Development; Effectiveness; Frequencies; Goals; Growth; HIV; Hepatitis B Virus; Hepatitis C virus; Host Defense; Immune; Immunologics; Individual; Infection; Infection Control; Instruction; Interleukin-2; Lymphocytic choriomeningitis virus; Maintenance; Mediating; Modeling; Phase; Play; Population; Production; Public Health; Publishing; Regulation; Resistance; Role; Series; Shapes; Signal Transduction; Source; Stat5 protein; Structure; System; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Viral; Virus; Virus Diseases; acute infection; anti-viral efficacy; chronic infection; cytokine; defined contribution; design; exhaust; exhaustion; immune checkpoint blockade; immunopathology; improved; innovation; insight; manufacture; permissiveness; progenitor; response; restoration; trait

PROJECT SUMMARY The overarching goals of this proposal are to define how intrinsic IL-2 production and extrinsic IL-2 signals act in conjunction with helper CD4 T cell subsets to configure the exhausted CD8 T cell pool during chronic viral infections and ascertain how these factors contribute to the restoration of responses following checkpoint blockade therapies. This is significant for providing both fundamental insights into the regulation of exhausted T cell ontogeny as well as for devising strategies to structure this ensemble to improve infection control while avoiding immunopathology. The premise is founded in part on a series of exciting published and preliminary findings showing that the pace of viral control can be predicted by the number of IL-2 producing CD8 T cells present at the peak of the effector phase of the anti-viral response. Moreover, the initial formation of IL-2 producing CD8 T cells is accelerated during the earliest stages of chronic viral infections, but this population fails to amplify, suggesting that they may instead serve as progenitors for the development of transitional and terminally exhausted subsets. We also discovered that IL-2-producing effector CD8 T cells generated during acute infections have superior protective powers and are resistant to full terminal exhaustion following adoptive transfer and chronic viral challenge. Additionally, our preliminary findings demonstrate that the cell-autonomous synthesis of IL-2 attenuates the ability to receive STAT5 signals. Collectively, these findings are consistent with a model in which the initial manufacture of IL-2 enables exhausted precursor formation by restricting STAT5- mediated signals, which are known to drive terminal differentiation. Further, we anticipate that the subsequent extinguishment of IL-2 synthesis restores permissiveness to STAT5 signaling, which prompts the further developmental transition of these precursors into more exhausted sub-populations. Our studies are designed to pin-point how intrinsic cytokine production and extrinsic cytokine signals direct the formation and maintenance of exhausted subsets, and provide new insights into the mechanisms that shape the efficacy of the anti-viral T cell pool during chronic infections. We propose the following specific aims: 1. Define the contributions of IL-2-producing CD8 T cells to the formation of exhausted subsets. 2. Define the influence of functionally distinct CD4 helper subsets on the exhausted pool. 3. Determine the temporally distinct roles of IL-2 in structuring the exhausted pool. Our studies take advantage of innovative and technically robust approaches to deconvolute the roles of distinct cytokine producing subsets of anti-viral T cells during chronic infections. They are designed to impact the field by advancing our understanding of how intrinsic cytokine production and extrinsic cytokine and cellular signals integrate to configure the exhausted CD8 T cell pool and contribute to the control of chronic viral infections.

项目摘要 该提案的总体目标是定义固有的IL-2生产和外部IL-2信号法 与辅助CD4 T细胞子集结合使用，以在慢性病毒期间配置耗尽的CD8 T细胞池 感染并确定这些因素如何导致检查点后响应的恢复 封锁疗法。这对于为耗尽的调节提供了两种基本见解很重要 T细胞个体发育以及制定策略以构建这种整体以改善感染控制 避免免疫病理学。该前提部分建立在一系列令人兴奋的发表和初步的基础上 调查结果表明，可以通过产生CD8 T细胞的IL-2数量来预测病毒控制的速度 存在于抗病毒反应的效应阶段的峰值。此外，IL-2的初始形成 在慢性病毒感染的最早阶段产生CD8 T细胞加速，但该种群失败 放大，表明它们可以作为过渡和发展的祖细胞 终止耗尽的子集。我们还发现，产生的IL-2产生效应子CD8 T细胞 急性感染具有优越的保护能力，并且具有抗管后的全终末疲劳性 转移和慢性病毒挑战。此外，我们的初步发现表明细胞自主 IL-2的合成减弱了接收STAT5信号的能力。总的来说，这些发现与 初始生产IL-2的模型可以通过限制STAT5-来实现耗尽的前体形成 介导的信号，已知会驱动终端分化。此外，我们预计随后的 IL-2合成的熄灭恢复了对STAT5信号的允许，这进一步促使 这些前体向更耗尽的子人群的发展过渡。我们的研究被设计为 针对内在的细胞因子产生和外在细胞因子如何指导形成和维护 精疲力尽的子集，并提供有关塑造抗病毒T的机制的新见解 慢性感染期间的细胞池。我们提出以下具体目标： 1。定义产生IL-2的CD8 T细胞对耗尽子集的形成的贡献。 2。定义功能上不同的CD4辅助子集对耗尽的池的影响。 3。确定IL-2在构造耗尽的池中的时间上不同的作用。 我们的研究利用了创新和技术上强大的方法来宣传不同的角色 慢性感染期间的细胞因子产生抗病毒T细胞子集。它们旨在影响领域 通过促进我们对内在细胞因子产生以及外在细胞因子和细胞信号的理解 集成以配置耗尽的CD8 T细胞池，并有助于控制慢性病毒感染。