The role of STAT3 in effector and memory CD8 T cell longevity and metabolism

描述(申请人提供)：记忆性CD8 T细胞由于其增强的寿命、增殖能力和功能潜力，可以提供对再次感染的异常长期的保护性免疫力。在病毒感染期间，激活的CD8T细胞克隆扩张并获得细胞毒功能以消除感染。然而，病毒清除后，抗病毒效应器CD8T细胞就会休息，停止分裂和合成抗病毒蛋白。一部分效应细胞分化成熟为保护性记忆CD8 T细胞，这些细胞寿命长，具有高增殖潜力，可以通过体内平衡增殖来补充记忆池。最近的工作表明，这种有效的记忆(E‘M)转换需要代谢切换，从主要依赖葡萄糖和糖酵解的合成代谢、快速分裂状态(由PI3K/AKT/mTOR途径驱动)到依赖脂肪酸/脂肪酸氧化的分解代谢静止状态(FAO；由FOXO/AMPK活性驱动)。然而，这个模型需要大量的研究，因为人们对记忆CD8 T细胞的代谢状态知之甚少，哪些信号调节这一过程，以及这如何影响它们的寿命和功能。也许更重要的是，我们需要更好地了解CD8 T细胞代谢的变化是如何与免疫反应中的T细胞分化相协调的。我们假设STAT3处于这两个过程的十字路口，因为它既是控制记忆T细胞分化的转录因子，也是调节线粒体呼吸的线粒体蛋白。我们的初步数据显示，在急性病毒感染期间，IL-21/IL-10/STAT3信号对记忆性CD8+T细胞的发育至关重要。在缺乏IL-21和IL-10或STAT3的情况下，病毒特异性CD8+T细胞保持终末效应(TE)分化状态，不能成熟为具有保护再感染和包含自我更新的中医细胞的功能性记忆T细胞。因此，在急性LCMV感染后，STAT3的活性驱动了E`M的转变，是功能性、保护性记忆CD8T细胞形成所必需的。此外，我们有数据表明，STAT3既控制着与记忆性CD8 T细胞分化有关的关键转录因子的表达，也控制着调节记忆性T细胞代谢、分化、功能和存活的PI3K/AKT/mTOR和AMPK通路的活性。这些数据表明，STAT3整合了各种信号，协调调节T细胞分化和代谢。我们这项研究的主要目的是确定STAT3是否调节记忆性CD8 T细胞分化过程中的合成代谢开关。为了研究这一点，我们将确定(1)PI3K/AKT/mTOR活性是否异常增加，以及(2)STAT3是否控制病毒特异性CD8T细胞的糖酵解、氧化呼吸和脂肪酸氧化。最后，我们将(3)比较核和线粒体STAT3在记忆性CD8 T细胞发育、代谢和基因表达中的作用。)) 与公共健康相关：T细胞的代谢状态控制其分化、增殖和存活的能力，最近优雅的研究表明，记忆CD8 T细胞形成和持续的能力取决于其从合成代谢状态转换到分解代谢状态的能力，利用脂肪酸氧化作为ATP生产的主要方式。这项资助将研究STAT3作为转录因子和线粒体蛋白在这一过程中所扮演的双重角色，以协调记忆CD8 T细胞的分化和新陈代谢。这项工作可以揭示多种调节淋巴细胞代谢和记忆T细胞生成的新机制，这些机制可以促进疫苗开发和基于T细胞的免疫治疗，以及我们对糖尿病、肥胖和老龄化的理解。)

DESCRIPTION (provided by applicant): Memory CD8 T cells can provide exceptionally long-term protective immunity against reinfection due to their enhanced longevity, proliferative capacity and functional potential. During a viral infection, the activated CD8 T cells clonally expand and acquire cytotoxic function to eliminate infection. However, after viral clearance, antiviral effector CD8 T cells "rest down" and stop dividing and synthesizing antiviral proteins. A portion of the effector cells differentiate and mature into protective memory CD8 T cells that are long-lived, have a high proliferative potential and can replenish the memory pool by homeostatic proliferation. Recent work suggests that this effector`memory (E`M) transition requires a metabolic switch from an anabolic, rapidly dividing state that relies primarily on glucose and glycolysis (driven by the PI3K/AKT/mTOR pathway) to a catabolic, quiescent state that relies on fatty acids/ fatty acid oxidation (FAO; driven by Foxo/AMPK activity). However, this model requires substantial investigation because very little is known about memory CD8 T cell metabolic states, which signals regulate this process and how this affects their lifespan and function. Perhaps more importantly, we need to better understand how changes in CD8 T cell metabolism are coordinated with T cell differentiation during immune responses. We hypothesize that STAT3 lies at the cross roads of these two processes because it is both a transcription factor that controls memory T cell differentiation and a mitochondrial protein that modulates mitochondrial respiration. Our preliminary data show that IL-21/IL-10/STAT3 signaling is essential for memory CD8+ T cell development during an acute viral infection. In absence of either IL-21 and IL-10 or STAT3, virus-specific CD8+ T cells retain terminal effector (TE) differentiation states and fail to mature into functional memory T cells that protect against reinfection and contain self-renewing TCM cells. Thus, STAT3 activity drives the E`M transition and is necessary for functional, protective memory CD8 T cells to form after acute LCMV infection. Additionally, we have data suggesting that STAT3 controls both the expression of key transcription factors involved in memory CD8 T cell differentiation and the activity of the PI3K/AKT/mTOR and AMPK pathways that regulate memory T cell metabolism, differentiation, function and survival. These data suggest STAT3 integrates various signals and coordinately regulates both T cell differentiation and metabolism. Our primary aim in this proposal is to determine if STAT3 regulates an anabolic ` catabolic switch during memory CD8 T cell differentiation. To study this, we will determine whether (1) PI3K/AKT/mTOR activity is abnormally increased and, reciprocally, if AMPK activity is decreased in Stat3-/- virus-specific CD8 T cells and (2) if STAT3 controls glycolysis, oxidative respiration and fatty acid oxidation in virus-specific CD8 T cells. Lastly, we will (3) compare the roles of nuclear and mitochondrial STAT3 in memory CD8 T cell development, metabolism and gene expression. ) ) PUBLIC HEALTH RELEVANCE: A T cell's metabolic state controls its ability to differentiate, proliferate and survive, and recent elegant studies have suggested that the ability of a memory CD8 T cell to form and persist depends on its ability to switch from an anabolic to catabolic state, utilizing fatty acid oxidation as the major mode of ATP production. This grant will examine the dual roles that STAT3 plays in this process both as a transcription factor and a mitochondrial protein to coordinate the differentiation and metabolism of memory CD8 T cells. This work could uncover multiple novel mechanisms for regulating lymphocyte metabolism and the generation of memory T cells that could enhance vaccine development and T cell based immunotherapies as well as our understanding of diabetes, obesity and aging. )