Resistance to T cell exhaustion

抵抗 T 细胞耗竭

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该提案的总体目标是定义内在 IL-2 产生和外在 IL-2 信号如何发挥作用与辅助 CD4 T 细胞亚群结合，在慢性病毒感染期间配置耗尽的 CD8 T 细胞库感染并确定这些因素如何有助于检查点后恢复反应封锁疗法。这对于提供对耗尽监管的基本见解具有重要意义 T 细胞个体发育以及设计策略来构建该整体以改善感染控制，同时避免免疫病理学。该前提部分建立在一系列令人兴奋的已发表和初步研究的基础上研究结果表明，病毒控制的速度可以通过产生 IL-2 的 CD8 T 细胞的数量来预测存在于抗病毒反应效应期的高峰期。此外，IL-2的初始形成在慢性病毒感染的最早阶段，CD8 T 细胞的产生速度会加快，但该细胞群却失败了放大，表明它们可能反而成为过渡和发展的祖先最终耗尽的子集。我们还发现，产生 IL-2 的效应 CD8 T 细胞在急性感染具有卓越的保护能力，并且在收养后能够抵抗完全的终末衰竭转移和慢性病毒挑战。此外，我们的初步研究结果表明，细胞自主 IL-2 的合成会减弱接收 STAT5 信号的能力。总的来说，这些发现与在该模型中，IL-2 的初始制造通过限制 STAT5- 来实现耗尽的前体形成介导信号，已知可驱动终末分化。此外，我们预计后续 IL-2合成的消除恢复了STAT5信号传导的许可性，这促使进一步这些前体的发育转变为更疲惫的亚种群。我们的研究旨在查明内在细胞因子的产生和外在细胞因子信号如何指导形成和维持耗尽的子集，并为塑造抗病毒 T 功效的机制提供新的见解慢性感染期间的细胞库。我们提出以下具体目标： 1. 定义产生 IL-2 的 CD8 T 细胞对耗尽亚群形成的贡献。 2. 定义功能不同的 CD4 辅助子集对耗尽池的影响。 3. 确定 IL-2 在构建耗尽池中在时间上的不同作用。我们的研究利用创新和技术上可靠的方法来解构不同的角色慢性感染期间产生抗病毒 T 细胞亚群的细胞因子。它们旨在影响该领域通过增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如何产生的理解整合以配置耗尽的 CD8 T 细胞库并有助于控制慢性病毒感染。