Understanding the influence of SREBP signaling on CD4 T helper cell biology

项目总结 这一应用的重点是理解脂质重新编程的分子机制 在CD4T辅助细胞亚群中的代谢，并评估类固醇代谢对T辅助细胞功能的影响。 越来越多的证据表明，CD4T辅助细胞迅速改变其代谢状态，以响应 TCR激活和细胞因子信号。这种重新编程是必要的，以匹配生物能量和 特定效应器功能的生物合成要求。一般来说，促炎症的CD4T细胞(如Th1和Th1) 获得一个强大的糖酵解程序，并将他们的新陈代谢转变为合成代谢状态。相比之下， 调节性T细胞在很大程度上依赖于脂肪酸氧化和大分子分解代谢来满足其 生物能量和生物合成要求。代谢编程中的这种区别似乎是必不可少的 以获得正常的T辅助细胞功能。辅助性T细胞代谢状态的遗传或药物调控 会削弱或加重特定的效应器功能。例如，强制执行糖酵解程序会扰乱 Tregs的抑制能力，并导致模型系统中自我容忍度的丧失。相比之下，强制执行 脂肪酸氧化代谢下调Th1和Th17细胞的促炎功能，从而 消病致病。这些观察结果导致了一种概念，即CD4T辅助细胞 代谢状态是效应器程序的基本组成部分。尽管收购的重要性显而易见 以及维持适当的代谢状态，T辅助细胞独特的分子机制 细胞获得必要的新陈代谢程序仍然知之甚少。在最近的工作中，我们已经确定了 固醇调节元件结合蛋白(SREBP1和SREB2)作为代谢重编程的关键调节因子 CD8T细胞。机械学研究表明，SREBPs由TCR信号激活，并驱动对 糖酵解和合成代谢。在缺乏SREBP活性的情况下，我们发现CD8T细胞无法 上调糖酵解通量和脂质合成，导致增殖能力减弱 效应器反应。这些数据使我们假设SREBPS将在 调节CD4T辅助细胞亚群分化和效应功能。为了支持这一假设，我们在 初步数据表明，SREBP程序的减弱选择性地干扰了Th1的体外分化 和Th17细胞，但不影响调节性T细胞的诱导，也不影响 体内Foxp3阳性Treg的产生/动态平衡因此，我们得出结论，SREBP信令在 在控制T辅助细胞亚群平衡方面的重要和以前未定义的作用。在此应用程序中，我们 对这些耐人寻味的初步数据进行扩展，并提出三个旨在阐明 SREBPs影响辅助性T细胞功能的分子机制(S)，并确定这些代谢 这些通路控制着自我耐受和自身免疫之间的平衡。

PROJECT SUMMARY This application is focused on understanding the molecular mechanisms underlying reprogramming of lipid metabolism in CD4 T helper subsets, and assessing the impact of sterol metabolism on T helper cell function. Accumulating evidence indicates that CD4 T helper cells rapidly change their metabolic state in response to TCR activation and cytokine signals. This reprogramming is necessary to match the bioenergetic and biosynthetic requirements of specific effector functions. In general pro-inflammatory CD4 T cells (e.g., Th1 and Th17) acquire a robust glycolytic program, and shift their metabolism towards an anabolic state. In contrast, regulatory T cells are largely reliant on fatty acid oxidation and macromolecule catabolism to meet their bioenergetic and biosynthetic requirements. This distinction in metabolic programming appears to be essential for proper T helper cell function. Genetic or pharmacologic manipulation of a T helper cell's metabolic state can attenuate or exacerbate specific effector functions. For example, enforcing a glycolytic program perturbs the suppressive ability of Tregs, and results in a loss of self-tolerance in models systems. In contrast, enforcing fatty acid oxidative metabolism downregulates the pro-inflammatory function of Th1 and Th17 cells, thereby attenuating disease pathogenesis. These observations have led to the concept that a CD4 T helper cells metabolic state is a fundamental component of the effector program. Despite the clear importance of acquiring and maintaining the appropriate metabolic state, the molecular mechanisms underlying how distinct T helper cells acquire the requisite metabolic programs remain poorly understood. In recent work we have identified the sterol regulatory element binding proteins (SREBP1 and 2) as critical regulators of metabolic reprogramming in CD8 T cells. Mechanistic studies revealed that SREBPs are activated by TCR signals and drive acquisition of glycolysis and anabolic metabolism. In the absence of SREBP activity, we found that CD8 T cells were unable to upregulate glycolytic flux and synthesis of lipids, resulting in poor proliferative capacity and attenuated effector responses. These data have led us to hypothesize that SREBPs would play a critical function in regulating the CD4 T helper subset differentiation and effector function. In support of this hypothesis, we find in preliminary data that attenuation of the SREBP program selectively perturbs the in vitro differentiation of Th1 and Th17 cells, but does not influence induction of regulatory T cells, nor does it influence the generation/homeostasis of Foxp3-positive Tregs in vivo. Thus, we conclude that SREBP signaling plays an important and previously undefined role in controlling the balance of T helper subsets. In this application, we extend on these intriguing preliminary data and propose three integrated aims designed to elucidate the molecular mechanism(s) by which SREBPs influence T helper cell function, and determine if these metabolic pathways control the balance between self-tolerance and autoimmunity.