Metabolic control of regulatory T cell functional identity

调节性 T 细胞功能特性的代谢控制

• 批准号: 10677731
• 负责人: Greg M. Delgoffe
• 金额: $ 60.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677731
• 关键词: Acetylation; Affect; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; Binding; CD4 Positive T Lymphocytes; CTLA4 blockade; Cell physiology; Cells; Cellular biology; Chemosensitization; Coupling; Cues; Data; Disease; Enteral; Environment; Epigenetic Process; Equilibrium; Event; Exposure to; FOXP3 gene; Functional disorder; Genes; Genetic; Glucose; Gnotobiotic; Histones; Hyperactivity; Immune response; Immune system; Immunity; Immunologics; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Intestines; Lactate Transporter; Lactic acid; Lactobacillus; Link; Malignant Neoplasms; Measurement; Metabolic; Metabolic Control; Metabolism; Modeling; Mus; Normal tissue morphology; Nutrient; Pathology; Pathway interactions; Peripheral; Play; Predisposition; Regulatory T-Lymphocyte; Role; Shapes; Site; Small Intestines; Supporting Cell; System; T-Cell Proliferation; T-Lymphocyte; Tissues; Tumor-Derived; Work; alpha ketoglutarate; cancer cell; demethylation; design; dysbiosis; effector T cell; epigenome; glucose metabolism; gut inflammation; histone modification; immunomodulatory therapies; in vivo; in vivo Model; metabolic profile; microbiota; mouse model; novel; tool; transcription factor; tumor; tumor microenvironment; uptake

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.

项目概要/摘要 Treg 细胞在组织内富集，是其主要作用部位之一，并拥有许多 适应使他们能够茁壮成长并保持稳定的血统身份。这些关键功能之一是 代谢特征改变。我们探索了各种组织环境的新陈代谢如何，特别是 在肿瘤内，稳定调节性 T 细胞功能。肿瘤产生对人体有毒的局部代谢环境 传统的效应 T 细胞，但调节性 T 细胞在那里茁壮成长，具有高度增殖性和维持性 功能稳定。癌细胞的代谢紊乱和调节性 T 细胞功能的增强 相关：我们最近表明 Treg 细胞受到肿瘤衍生代谢物的支持，尤其是乳酸 酸。 Treg 细胞避开葡萄糖代谢，上调基因，使它们能够承受富含乳酸的环境 条件并利用这种代谢物来促进其功能。 Foxp3 限制性删除乳酸转运蛋白 单羧酸转运蛋白 1（MCT1，由 Slc16a1 编码）阻碍肿瘤内的 Treg 功能，导致 免疫更加活跃的环境。重要的是，CTLA-4 等 Treg 细胞靶向免疫疗法 封锁会促使 Treg 细胞利用葡萄糖而不是乳酸。值得注意的是，Treg 对葡萄糖的利用与对葡萄糖的利用相比。 乳酸不仅存在于肿瘤中，在小鼠的外周组织中也有发现。删除MCT1时 导致稳态时不产生自身免疫，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。即使在孤立的情况下，高葡萄糖浓度也会阻碍 Treg 细胞功能和稳定性，而乳酸可以防止这些分化事件。从机械上来说， 乳酸广泛支持 Treg 细胞增殖和功能，但乳酸等替代途径如何支持 Treg 细胞增殖和功能 代谢支持和驱动的 Treg 细胞身份仍不清楚。 Treg 细胞不仅仅由 Foxp3，而是依赖于支持其功能的已建立的表观遗传景观，无论是在哪里 Foxp3 不仅可以结合其他关键转录因子。现在很明显，代谢中间体发挥着关键作用 在表观遗传重塑中，组蛋白可以直接被代谢物修饰（乙酰化）或修饰 通过代谢过程（去甲基化需要αKG）。最近，乳酸本身已被证明可以直接 修饰组蛋白，尽管组蛋白乳酰化的表观遗传后果仍未完全描述。 我们的初步数据表明，Treg 细胞在 MCT1 依赖性细胞中具有升高的组蛋白乳酰化水平。 乳酰化增加的 Treg 细胞具有更稳定的 Treg 细胞特征。在这里我们将 解决了组织中富集的代谢物（尤其是乳酸）驱动调节性 T 细胞的假设 功能同一性，使用体内系统，其中 Treg 细胞要么处于不利的稳定状态（癌症），要么 努力控制免疫力（肠道炎症），将新型小鼠模型与功能性和 表观遗传学分析可用于分析这些稀有细胞。这项工作将改变我们对如何 代谢物等环境/组织特异性线索可以帮助塑造 Treg 细胞的功能和命运。