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

描述（由申请人提供）：记忆性CD 8 T细胞由于其增强的寿命、增殖能力和功能潜力，可以提供针对再感染的异常长期保护性免疫。在病毒感染期间，活化的CD 8 T细胞克隆扩增并获得细胞毒性功能以消除感染。然而，在病毒清除后，抗病毒效应CD 8 T细胞“休息”并停止分裂和合成抗病毒蛋白。一部分效应细胞分化并成熟为保护性记忆CD 8 T细胞，这些细胞寿命长，具有高增殖潜力，并且可以通过稳态增殖补充记忆库。最近的研究表明，这种效应记忆（E`M）转换需要从主要依赖于葡萄糖和糖酵解（由PI 3 K/AKT/mTOR途径驱动）的合成代谢、快速分裂状态转换为依赖于脂肪酸/脂肪酸氧化（FAO;由Foxo/AMPK活性驱动）的分解代谢、静止状态。然而，这个模型需要大量的研究，因为对记忆CD 8 T细胞代谢状态知之甚少，哪些信号调节这个过程，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CD 8 T细胞代谢的变化如何在免疫应答期间与T细胞分化协调。我们假设STAT 3位于这两个过程的交叉点，因为它既是控制记忆T细胞分化的转录因子，又是调节线粒体呼吸的线粒体蛋白。 我们的初步数据显示，IL-21/IL-10/STAT 3信号传导对于急性病毒感染期间记忆性CD 8 + T细胞发育至关重要。在不存在IL-21和IL-10或STAT 3的情况下，病毒特异性CD 8 + T细胞保持终末效应子（TE）分化状态，并且不能成熟为功能性记忆T细胞，所述功能性记忆T细胞保护免于再感染并且含有自我更新的TCM细胞。因此，STAT 3活性驱动E`M转换，并且是在急性LCMV感染后形成功能性、保护性记忆CD 8 T细胞所必需的。此外，我们有数据表明，STAT 3控制参与记忆性CD 8 T细胞分化的关键转录因子的表达以及调节记忆性T细胞代谢、分化、功能和存活的PI 3 K/AKT/mTOR和AMPK途径的活性。这些数据表明STAT 3整合了多种信号并协调调节T细胞分化和代谢。我们的主要目的是确定STAT 3是否在记忆性CD 8 T细胞分化过程中调节合成代谢“分解代谢开关”。为了研究这一点，我们将确定（1）在Stat 3-/-病毒特异性CD 8 T细胞中PI 3 K/AKT/mTOR活性是否异常增加，以及AMPK活性是否降低，以及（2）STAT 3是否控制病毒特异性CD 8 T细胞中的糖酵解、氧化呼吸和脂肪酸氧化。最后，我们将（3）比较核和线粒体STAT 3在记忆性CD 8 T细胞发育、代谢和基因表达中的作用。) )

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. ) )