Resistance to T cell exhaustion

项目摘要 该建议的首要目标是确定内源性IL-2产生和外源性IL-2信号如何起作用 联合辅助性CD4 T细胞亚群，以在慢性病毒性肝炎期间配置耗尽的CD8 T细胞库。 感染，并确定这些因素如何有助于恢复检查点后的反应 封锁疗法这对于提供对耗尽的监管的基本见解， T细胞个体发育以及设计策略来构建该集合以改善感染控制， 避免免疫病理学。前提是建立在一系列令人兴奋的出版和初步的 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 存在于抗病毒应答的效应期的峰值。此外，IL-2的初始形成 在慢性病毒感染的早期阶段，CD8 T细胞的产生加速，但这一群体未能 放大，这表明他们可能会作为祖先的发展过渡， 最终耗尽的子集。我们还发现，IL-2产生的效应CD8 T细胞， 急性感染具有优越的上级保护能力， 转移和慢性病毒攻击。此外，我们的初步研究结果表明，细胞自主 IL-2的合成减弱了接收STAT 5信号的能力。总的来说，这些发现与 一种模型，其中IL-2的初始制造通过限制STAT5- 介导的信号，这是已知的驱动终端分化。此外，我们预计， IL-2合成的抑制恢复了对STAT5信号传导的容许性，这促进了进一步的细胞凋亡。 这些前体向更疲惫的亚群的发育过渡。我们的研究旨在 精确点如何内在细胞因子的生产和外在细胞因子信号直接形成和维护 耗尽的子集，并提供了新的见解的机制，形状的抗病毒T 慢性感染时的细胞池我们提出以下具体目标： 1.定义IL-2产生的CD8 T细胞对耗竭亚群形成的贡献。 2.定义功能不同的CD4辅助细胞亚群对耗竭池的影响。 3.确定IL-2在构建耗尽池中的时间上不同的作用。 我们的研究利用创新的和技术上强大的方法来解卷积不同的作用， 在慢性感染期间，抗病毒T细胞的细胞因子产生亚群。它们旨在影响该领域 通过提高我们对内在细胞因子产生和外在细胞因子及细胞信号 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。

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.