Metabolic control of regulatory T cell functional identity

项目摘要/摘要 Treg细胞在组织中丰富，是其主要作用部位之一，并拥有许多 使它们茁壮成长并保持稳定的血统身份的适应。这些关键功能之一是 改变了新陈代谢特征。我们已经探索了各种组织环境的新陈代谢，特别是 在肿瘤内，稳定调节性T细胞功能。肿瘤会产生一种局部代谢环境，对 传统的效应性T细胞，但调节性T细胞在那里茁壮成长，高度增殖并保持 性能稳定。癌细胞的代谢紊乱和调节性T细胞功能的增强 关联：我们最近表明，Treg细胞由肿瘤来源的代谢物支持，最明显的是乳酸 酸。Treg细胞避开葡萄糖代谢，上调基因，使其能够抵抗富含乳酸的 条件，并利用这种代谢物来补充他们的功能。Foxp3限制性乳酸转运蛋白的缺失 单羧酸转运体1(MCT1，由Slc16a1编码)，阻碍肿瘤内Treg功能，导致 一个更活跃的免疫环境。重要的是，像CTLA-4这样的Treg细胞靶向免疫疗法 Blockade促使Treg细胞利用葡萄糖而不是乳酸。值得注意的是，Treg对葡萄糖的利用与 乳酸不仅限于肿瘤，在小鼠的外周组织中也有发现。删除MCT1时 导致在稳定状态下没有自身免疫，MCT1缺陷的Treg细胞无法充分控制 T细胞转移模型中的肠道炎症。即使在与世隔绝的情况下，高葡萄糖浓度也会阻碍 Treg细胞的功能和稳定性，而乳酸可以保护这些分化事件。从机械上讲， 乳酸广泛支持Treg细胞的增殖和功能，但像乳酸这样的替代途径 新陈代谢支持和驱动Treg细胞的身份仍不清楚。Treg细胞不是单独由 Foxp3，而是依赖于支持它们功能的已建立的表观遗传格局，在Foxp3 可以结合其他关键转录因子。现在很明显，代谢中间体起着关键作用。 在表观遗传重塑中，组蛋白可被代谢物直接修饰(乙酰化)或修饰 通过代谢过程(去甲基化需要αKG)。最近，乳酸盐本身已被证明直接 修饰组蛋白，尽管组蛋白乳糖化的表观遗传后果仍未完全描述。 我们的初步数据表明，在依赖于MCT1的TREG细胞中，组蛋白乳糖化水平升高 乳糖化程度增加的Treg细胞具有更稳定的Treg细胞特征。在这里，我们将 解决这样一种假设，即组织中富含的代谢物，最明显的是乳酸，可以驱动调节性T细胞 功能鉴定，使用体内系统，其中Treg细胞要么不利于稳定(癌症)，要么 努力控制免疫(肠道炎症)，将新的小鼠模型与功能性和 表观遗传学分析对描述这些稀有细胞是可行的。这项工作将改变我们对如何 环境/组织特定的线索，如代谢物，可以帮助塑造Treg细胞的功能和命运。

PROJECT SUMMARY/ABSTRACT Treg cells are enriched within the tissues, one of their main sites of action and possess a number of adaptations that allow them to thrive and maintain a stable lineage identity. One of these critical features is an altered metabolic profile. We have explored how the metabolism of various tissue environments, especially within tumors, stabilize regulatory T cell function. Tumors produce a local metabolic environment that is toxic to conventional, effector T cells, but regulatory T cells thrive there, being highly proliferative and maintaining stable function. Metabolic derangement of cancer cells and the potentiation of regulatory T cell function are linked: we have recently shown that Treg cells are supported by tumor-derived metabolites, most notably lactic acid. Treg cells eschew glucose metabolism, upregulating genes allowing them to withstand lactic acid-rich conditions and utilize this metabolite to fuel their function. Foxp3-restricted deletion of the lactate transporter monocarboxylate transporter 1 (MCT1, encoded by Slc16a1), hindered Treg function within tumors, resulting in a more immunologically active environment. Importantly, Treg cell-targeting immunotherapies like CTLA-4 blockade drives Treg cells to utilize glucose rather than lactate. Notably, this Treg utilization of glucose vs. lactate was not limited to tumors, but also found in the peripheral tissues of mice. While deletion of MCT1 resulted in no autoimmunity at the steady state, MCT1-deficient Treg cells were unable to sufficiently control intestinal inflammation in a T cell transfer model. Even in isolation, high glucose concentrations can hinder Treg cell function and stability, while lactate can protect against these differentiation events. Mechanistically, lactate broadly supports Treg cell proliferation and function, but how alternative pathways like lactate metabolism support and drive Treg cell identity remains unclear. Treg cells are not solely programmed by Foxp3, but rather rely on an established epigenetic landscape that supports their function, both in where Foxp3 can bind but also other key transcription factors. It now is clear that metabolic intermediates play critical roles in epigenetic remodeling, as histones can be either directly modified by metabolites (acetylation) or modified through metabolic processes (demethylation requiring αKG). Recently, lactate itself has been shown to directly modify histones, although the epigenetic consequences of histone lactylation remain incompletely described. Our preliminary data suggest that Treg cells harbor elevated lactylation of histones in an MCT1-dependent manner, and that Treg cells with increased lactylation harbor a more stable Treg cell signature. Here we will address the hypothesis that metabolites, most notably lactate, enriched in the tissues drive regulatory T cell functional identity, using in vivo systems in which Treg cells are either unfavorably stabilized (cancer) or struggle to control immunity (intestinal inflammation), coupling novel mouse models with functional and epigenetic analyses feasible to profile these rare cells. This work will transform our understanding of how context/tissue-specific cues like metabolites can help shape Treg cell function and fate.