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.

项目摘要/摘要 treg细胞在组织中富集，它们的主要作用之一，拥有许多 适应他们蓬勃发展并保持稳定的谱系身份。 改变了代谢剖面。 在肿瘤中，稳定调节性T细胞功能。 常规的效应T细胞，但在那里调节蓬勃发展，高度增殖和MainD维护 稳定的功能。 链接：我们最近表明Treg细胞受肿瘤来源的代谢，最著名的是乳酸 酸性细胞避开了葡萄糖代谢，上调基因，使其能够承受富含乳酸的含量。 条件和美国代谢产物供油。 单羧酸盐转运蛋白1（MCT1，由SLC16A1编码），阻碍treg功能WITIN肿瘤，重新占领 更重要的是具有免疫学的环境。 封锁驱动Treg细胞利用葡萄糖而不是乳酸。 乳酸不限于肿瘤，而在小鼠的周围组织中也发现。 在稳态下没有自身免疫性，MCT1缺陷treg细胞足够控制 T细胞转移模型中的肠道炎症。 Treg细胞功能和稳定性，而乳酸可以保护这些差异事件。 乳酸广泛支持Treg细胞的累积性和功能，但属于乳酸等替代途径 代谢支持和驱动Treg细胞身份尚不清楚。 foxp3，但却依靠一个支持其功能的已建立的表观遗传景观，都是foxp3 可以绑定钥匙转录因子。 在表观遗传重塑中，震惊可以通过代谢物（乙酰化）直接修饰或修饰 通过代谢过程（最近需要αkg的脱甲基化）。 修饰组蛋白，垂直于组蛋白乳糖化的表观遗传奉献仍然不完全描述。 我们的初步数据表明，Treg细胞在MCT1依赖性中具有升高组蛋白的乳酸化升高 方式，乳酸化增加的Treg细胞具有更稳定的Treg细胞特征。 解决了以下假设：最著名的是乳酸，富含组织驱动调节剂的代谢产物。 功能身份，使用体内系统，其中Treg细胞是不利的稳定（癌症） 努力控制免疫力（肠炎），将新颖的小鼠模型耦合 表观遗传学分析可为这些稀有细胞提供可行的方式。 上下文/组织特异性提示（例如代谢产物）可以帮助塑造Treg细胞功能和命运。