Mitochondrial Membrane Dynamics in Th17 Cells

Th17 细胞的线粒体膜动力学

• 批准号: 10733013
• 负责人: Erika L Pearce
• 金额: $ 57.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733013
• 关键词: Address; Antigens; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; CNS autoimmune disease; Cell Death; Cell Differentiation process; Cell physiology; Cells; Cellular Metabolic Process; Complex; Crista ampullaris; Data; Disease; Effector Cell; Electron Transport; Environment; Epigenetic Process; Event; Experimental Autoimmune Encephalomyelitis; Failure; Generations; Genes; Genetic Transcription; Goals; Growth; Health; IL17 gene; Immune; Immune System Diseases; Immune Targeting; Immune response; Immunobiology; Impairment; In Vitro; Infection; Inflammation; Inner mitochondrial membrane; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Membrane; Membrane Fusion; Memory; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial DNA; Monomeric GTP-Binding Proteins; Morphology; Mus; OPA1 gene; Organelles; Outer Mitochondrial Membrane; Output; Pathology; Phenotype; Process; Production; Proliferating; Protein Family; Proteins; Regulatory T-Lymphocyte; Resistance; Rest; Role; STK11 gene; Shapes; Signal Transduction; Stress; Structure; T cell differentiation; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Work; cell growth regulation; cell type; cytokine; environmental change; experimental study; food consumption; gut homeostasis; in vivo; insight; migration; mitochondrial membrane; mitochondrial metabolism; programs; respiratory; response; restraint; therapeutic target; transcription factor

PROJECT SUMMARY The extensive changes in phenotype and function observed in T cells upon activation are intimately linked to changes in cellular metabolism. The failure to engage specific and appropriate metabolic programs can impair or alter T cells, and thus lead to ineffective, or even overexuberant, immune responses. Central to metabolism are mitochondria, which serve as central hubs of energy generation and biosynthetic activity. Work from our group and others has provided mechanistic insights into how mitochondrial metabolism is critical to T cell differentiation and function. However, knowledge about why these organelles change shape to maintain metabolism, biosynthetic capacity, and function, and in what ways mitochondrial remodeling influences T cell activation, differentiation, or effector molecule expression is lacking. Investigating how dynamic changes in mitochondria regulate metabolism to impact CD4+ T cells will enhance our fundamental understanding of immunobiology and of how to manipulate these cells for disease therapy in the context of cancer, infection, and autoimmunity. In our initial experiments we found that unlike other Th cell subsets, Th17 cells, a cell type necessary for maintaining gut homeostasis and implicated in certain types of autoimmunity and inflammation, had elongated mitochondria in a fused network, as well as tight cristae morphology. These results suggested a differential role for mitochondrial fusion and the protein OPA1, which mediates both membrane fusion and cristae morphology, in these cells. OPA1 deletion had no discernible effect on Th1 and Th2 cell differentiation or cytokine production in vitro, and while Th17 cell differentiation was also unimpaired, IL-17 expression was drastically reduced. Further, mice with a T cell-specific OPA1 deletion were resistant to developing pathology in experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated autoimmune disease of the central nervous system. Finally, our data revealed a role for liver kinase B1 (LKB1) in regulating the cellular response to OPA1-deficiency, and in restraining Th17 cell IL-17 expression when mitochondrial fusion is perturbed. In this proposal we now seek to understand how mitochondrial dynamics influence the function of diverse CD4+ T cell subsets. Our overall goal is to dissect the function of OPA1 in Th17 cell effector function, as well as probe its potential role other CD4+ T cell subsets, and to determine how MM fusion interfaces with LKB1 signaling to modulate cellular metabolism to limit IL-17 expression in settings of mitochondrial disruption or stress in vitro and in vivo. To this end, we propose to 1) explore the role of mitochondrial dynamics in CD4+ Th cells, 2) determine the extent to which LKB1 controls the cellular response to OPA1-deficiency in Th17 cells, and 3) investigate how metabolic changes upon disrupting mitochondrial fusion lead to dampened Th17 cell function.

项目摘要 激活后T细胞中观察到的表型和功能的广泛变化与 细胞代谢的变化。未能参与特定且适当的代谢计划会损害 或改变T细胞，从而导致无效，甚至过度效应的免疫反应。代谢的核心 是线粒体，它是能量产生和生物合成活性的中心枢纽。我们的工作 小组和其他人提供了有关线粒体代谢如何至关重要的机械见解 分化和功能。但是，了解为什么这些细胞器会改变形状以维护 代谢，生物合成能力和功能，线粒体重塑以什么方式影响T细胞 缺乏激活，分化或效应分子表达。调查动态变化 线粒体调节代谢以影响CD4+ T细胞，将增强我们对 免疫生物学以及如何在癌症，感染和 自身免疫性。在最初的实验中，我们发现与其他细胞子集Th17细胞（一种细胞类型）不同 维持肠道稳态所必需的，并与某些类型的自身免疫和炎症有关 在融合网络中细长的线粒体以及紧密的Cristae形态。这些结果表明 线粒体融合和蛋白OPA1的差异作用，它介导膜融合和Cristae 形态，在这些细胞中。 OPA1缺失对TH1和TH2细胞分化或细胞因子没有明显的影响 在体外产生，尽管Th17细胞分化也没有受损，但IL-17表达却急剧。 减少。此外，具有T细胞特异性OPA1缺失的小鼠对发展病理具有抵抗力 实验性自身免疫性脑脊髓炎（EAE），一种Th17细胞介导的中枢的自身免疫性疾病 神经系统。最后，我们的数据揭示了肝激酶B1（LKB1）在调节细胞反应中的作用 当线粒体融合受到干扰时，要进行OPA1缺乏效率，并限制Th17细胞IL-17的表达。在这个 提案我们现在试图了解线粒体动力如何影响各种CD4+ T细胞的功能 子集。我们的总体目标是剖析OPA1在Th17细胞效应子函数中的功能，并探测其 潜在角色其他CD4+ T细胞子集，并确定MM融合界面如何使用LKB1信号传导 调节细胞代谢以限制IL-17在线粒体破坏或体外应力的设置中的表达 和体内。为此，我们建议1）探索线粒体动力学在CD4+ TH细胞中的作用，2） 确定LKB1控制TH17细胞中对OPA1缺陷的细胞反应的程度，3） 研究中代谢变化如何破坏线粒体融合会导致Th17细胞功能降低。