Resistance to T cell exhaustion

项目总结 这项提议的首要目标是定义内在的IL-2产生和外在的IL-2信号如何起作用 与辅助者CD4T细胞亚群一起配置慢性病毒期间耗尽的CD8T细胞池 感染，并确定这些因素如何有助于检查站后反应的恢复 封锁疗法。这对于提供对精疲力竭的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这个整体以改善感染控制，同时 避免免疫病理学。这一前提部分建立在一系列激动人心的出版和初步的 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 处于抗病毒反应的效应期的顶峰。此外，IL-2的初步形成 在慢性病毒感染的早期阶段，CD8T细胞的产生被加速，但这一群体失败了 来放大，这表明它们可能相反地成为过渡和发展的先驱 终端耗尽的子集。我们还发现，产生IL-2的效应器CD8 T细胞在 急性感染具有更强的保护力，并能抵抗收养后的全部终末衰竭 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。总体而言，这些发现与 一种模型，在该模型中，IL-2的初始制造通过限制STAT5-5来实现耗尽的前体形成 中介信号，已知的驱动末端分化的信号。此外，我们预计随后的 IL-2合成的消失恢复了对STAT5信号的通透性，这促使进一步 这些前体向更疲惫的亚群的发育转变。我们的研究旨在 内源性细胞因子的产生和外源性细胞因子信号如何指导细胞的形成和维持 并为形成抗病毒T细胞疗效的机制提供了新的见解 慢性感染期间的细胞池。我们提出了以下具体目标： 1.明确产生IL-2的CD8 T细胞在衰竭亚群形成中的作用。 2.定义功能上不同的CD4辅助子集对耗尽池的影响。 3.确定IL-2在构建耗竭池中的时间不同作用。 我们的研究利用创新和技术稳健的方法来揭示不同的 慢性感染期间产生抗病毒T细胞亚群的细胞因子。他们的设计是为了影响这个领域 通过促进我们对内在细胞因子的产生以及外源性细胞因子和细胞信号的理解 整合以配置耗尽的CD8 T细胞池，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.