Targeting mitochondrial regulator MCJ to enhance CD8 cell immune response

靶向线粒体调节剂 MCJ 增强 CD8 细胞免疫反应

基本信息

批准号：
10293952
负责人：
Mercedes Rincon
金额：
$ 31.64万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10293952
关键词：
ATP Synthesis Pathway Address Affect Antigens Area CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Cellular Metabolic Process Citric Acid Cycle Communicable Diseases Cytoplasmic Granules Cytosol Dose Engineering Feeds Generations Glucose Glutamine Glycolysis Glycolysis Inhibition Goals Human Immune Immune response Immune system Immunology Immunotherapy In Vitro Inner mitochondrial membrane Integral Membrane Protein Knockout Mice Lead Malignant Neoplasms Mediating Membrane Potentials Memory Metabolic Metabolic Pathway Metabolism Methylation Mind Mitochondria Modeling Mus NADH dehydrogenase (ubiquinone)Nonesterified Fatty Acids Nucleotide Biosynthesis Oxidative Phosphorylation Pathway interactions Production Protein Deficiency Proteins Respiration Role Source T-Lymphocyte Testing Therapeutic Tissues Vaccination Vaccines Viral Vaccines Xenograft Model anti-tumor immune response arm cancer immunotherapy clinically relevant contextual factors cytokine cytotoxic cytotoxicity fatty acid oxidation healthy volunteer immune function improved in vivo influenza infection influenzavirus interest metabolic abnormality assessment mitochondrial membrane mitochondrial metabolism mouse model neoplastic cell novel strategies novel therapeutics protein expression response translational impact

项目摘要

PROJECT SUMMARY Metabolism is now considered as a major regulatory factor of the function of immune cells and influences the course of an immune response. Studying how metabolic changes in immune cells have an effect on the immune response is becoming a major area of interest in immunology. Control of T cell metabolism is emerging as an alternative strategy to modulate the immune response, either to increase or decrease the strength of the immune response. Novel approaches to modulate the metabolism of T cells will be therefore highly beneficial. A number of studies have shown that both CD4 and CD8 cells undergo a reprogramming of their metabolic pathways that lead to the generation of ATP as the main source of metabolic energy. Thus, in those circumstances where the goal is to therapeutically increase CD8 cell immune response (e.g. vaccines, cancer immunotherapy), promoting mitochondria activity without compromising the glycolytic pathway for expansion could be an ideal approach. Unfortunately, no good strategies have yet been identified to achieve this goal. We have recently identified MCJ (Methylation-Controlled J protein) as an endogenous negative regulator of Complex I of the electron transport chain (ETC). MCJ is abundantly expressed in CD8 cells, relative to other immune cells. We have shown that CD8 cells from MCJ KO mice have increased mitochondrial membrane potential, mitochondrial respiration and production of mitochondrial ATP, but normal glycolysis. Moreover, increased mitochondrial respiration promotes cytokine secretion as well as cytotoxic activity. Because of their dynamic aspect and ability to relocate in the cell, mitochondria are key to maintain ATP-rich microdomains within the cytosol. Thus, mitochondrial-derived ATP contributes to sustain specific energetically demanding cellular processes (high need for ATP) such as secretion of cytokines and granules. Importantly, using an influenza virus infection model we have shown that MCJ-deficient CD8 cells have superior protective capacity. We propose that MCJ could be a target to increase mitochondrial metabolism in CD8 cells to potentially enhance efficacy of CD8 cell-mediated vaccines and CD8 cell-mediated immunotherapy. Within the context of this application we propose to address 1) whether MCJ acts as a mitochondrial endogenous brake in human CD8 cells, and whether disrupting MCJ expression increases the ability of human CD8 cells to produce cytokines and kill target cells, 2) whether loss of MCJ can be used as a strategy to improve immunotherapy using mouse models. The results from the proposed studies will allow MCJ to emerge as a promising metabolic target to increase CD8 cell response and improve cancer immunotherapy efficacy.

项目概要代谢现在被认为是免疫细胞功能的主要调节因素并影响免疫细胞的功能。免疫反应的过程。研究免疫细胞的代谢变化如何影响免疫反应正在成为免疫学的一个主要兴趣领域。 T细胞代谢的控制是正在成为调节免疫反应的替代策略，以增加或减少免疫反应的强度。因此，调节 T 细胞代谢的新方法将是非常有益。许多研究表明，CD4 和 CD8 细胞都会经历以下重编程：它们的代谢途径导致 ATP 的产生，作为代谢能量的主要来源。因此，在目标是治疗性增强 CD8 细胞免疫反应的情况（例如疫苗、癌症免疫疗法），在不损害糖酵解途径的情况下促进线粒体活性扩张可能是一种理想的方法。不幸的是，目前还没有找到好的策略来实现这个目标。我们最近发现 MCJ（甲基化控制 J 蛋白）是一种内源性负调控蛋白电子传递链 (ETC) 复合物 I 的调节剂。 MCJ 在 CD8 细胞中大量表达，相对于其他免疫细胞。我们发现 MCJ KO 小鼠的 CD8 细胞有所增加线粒体膜电位、线粒体呼吸和线粒体 ATP 生成，但正常糖酵解。此外，线粒体呼吸的增加促进细胞因子的分泌以及细胞毒性活动。由于其动态方面和在细胞中重新定位的能力，线粒体是维持胞质内富含 ATP 的微结构域。因此，线粒体来源的 ATP 有助于维持特定的对能量要求较高的细胞过程（对 ATP 的高需求），例如细胞因子和颗粒的分泌。重要的是，使用流感病毒感染模型，我们发现 MCJ 缺陷的 CD8 细胞超强的防护能力。我们认为 MCJ 可能是增加线粒体代谢的目标 CD8细胞可能增强CD8细胞介导的疫苗和CD8细胞介导的功效免疫疗法。在本申请的背景下，我们建议解决 1) MCJ 是否充当人 CD8 细胞中线粒体内源性制动，以及破坏 MCJ 表达是否会增加人类CD8细胞产生细胞因子和杀伤靶细胞的能力，2）MCJ的缺失是否可以作为使用小鼠模型改进免疫治疗的策略。拟议研究的结果将使 MCJ 成为增强 CD8 细胞反应并改善癌症免疫治疗的有前景的代谢靶点功效。