Mitochondria regulate adaptive immunity

摘要 T细胞是获得性免疫反应和分解的主要介体。之前，我们发现激活了 T细胞也增加了它们线粒体的耗氧率；在缺乏关键的 T细胞是电子传递链中复合体III的亚单位，在体外和体内都不能被激活。 此外，我们发现，在T调节细胞(Treg细胞)特异性失活的复合体III，Treg细胞存活， 增殖，并维持稳定的Foxp3表达，但未能发挥作用，导致鳞屑样表型。 我们的发现确定线粒体是基本的常规和调节性T细胞的必要调节器 功能。根据我们之前的观察，一个中心问题是线粒体新陈代谢如何控制 常规T细胞和调节性T细胞都有功能。我们认为线粒体新陈代谢是 通过产生ETC依赖的活性氧发挥适应性免疫功能所必需的 (ROS)和TCA循环代谢产物的产生来控制转录因子和染色质/DNA 分别进行了修改。线粒体ETC复合体I和III是ROS产生的主要部位。 三氯乙酸循环酶可促进琥珀酸和L-2-羟基戊二酸(L-2HG)的合成以控制DNA 和组蛋白甲基化。因此，我们假设传统的CD8T细胞需要线粒体ROS来 激活和记忆分化；但记忆性CD8 T细胞的维持需要TCA周期 代谢物。此外，我们还推测线粒体TCA循环代谢产物通过 控制DNA甲基化。为了验证这一假设，我们提出了以下目标：具体目标I： 确定CD8 T细胞激活和记忆是否需要复合体I或III产生的ROS TCA循环代谢产物的形成对记忆的维持是必不可少的。具体目标二：确定 TCA循环代谢产物是否控制Treg细胞的抑制功能。这些目标加在一起将定义 线粒体决定T细胞命运和功能的机制。 1

Abstract T cells are major mediators of adaptive immune responses and resolution. Previously, we found that activated T cells also increase their rate of mitochondrial oxygen consumption; and that in the absence of a critical subunit of complex III within the electron transport chain, T cells failed to be activated in vitro or in vivo. Further, we found that upon T regulatory cell (Treg cell) specific inactivation of complex III, Treg cells survived, proliferated, and maintained stable Foxp3 expression but failed to function, resulting in a scurfy-like phenotype. Our findings identified mitochondria as necessary regulators of essential conventional and regulatory T cell functions. A central question based on our previous observations is how mitochondrial metabolism controls both conventional T cell and regulatory T cell function. We propose that mitochondrial metabolism is necessary for adaptive immune functions through the generation of ETC dependent reactive oxygen species (ROS) and production of TCA cycle metabolites to control transcription factors and chromatin/DNA modifications, respectively. Mitochondrial ETC complex I and III are the dominant sites of ROS generation. TCA cycle enzymes can elevate the production of succinate and L-2-hydroxygluatrate (L-2HG) to control DNA and histone methylation. Thus, we hypothesize that conventional CD8T cells require mitochondrial ROS for activation and memory differentiation; but that maintenance of memory CD8 T cells requires TCA cycle metabolites. Also, we postulate that mitochondrial TCA cycle metabolites control Treg suppressive function by controlling DNA methylation. To test this hypothesis, we propose the following aims: Specific Aim I: Determine whether complex I or III generated ROS are required for CD8 T cell activation, and memory formation while TCA cycle metabolites are essential for memory maintenance. Specific Aim II: Determine whether TCA cycle metabolites control Treg cell suppressive function. Together these aims will define the mechanisms by which mitochondria dictate T cell fate and function. 1