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

• 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
• 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

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.

项目摘要 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。研究免疫细胞中的代谢变化如何影响免疫细胞， 免疫应答正成为免疫学中主要的关注领域。控制T细胞代谢是 作为调节免疫应答的替代策略出现，以增加或减少免疫应答。 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细胞都经历了重编程， 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 目标是治疗性地增加CD8细胞免疫应答的那些情况（例如疫苗， 癌症免疫疗法），促进线粒体活性而不损害糖酵解途径， 扩大可能是一个理想的办法。不幸的是，目前还没有找到实现这一目标的好策略。 这个目标我们最近发现MCJ（甲基化控制的J蛋白）是一种内源性阴性 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。我们已经表明，来自MCJ KO小鼠的CD8细胞增加， 线粒体膜电位、线粒体呼吸和线粒体ATP产生，但正常 糖酵解此外，增加的线粒体呼吸促进细胞因子分泌以及细胞毒性细胞因子分泌。 活动由于它们的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的微区。因此，脑源性ATP有助于维持特定的 需要能量的细胞过程（对ATP的高需求），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，我们已经表明MCJ缺陷型CD8细胞具有 上级保护能力。我们认为MCJ可能是增加线粒体代谢的靶点， CD8细胞，以潜在地增强CD8细胞介导的疫苗和CD8细胞介导的疫苗的功效。 免疫疗法。在本申请的上下文中，我们提出解决1）MCJ是否充当 人CD8细胞中的线粒体内源性制动，以及破坏MCJ表达是否会增加 人CD8细胞产生细胞因子和杀死靶细胞的能力，2）MCJ的丧失是否可以用作免疫抑制剂。 使用小鼠模型改善免疫疗法的策略。拟议研究的结果将使MCJ 成为一个有前途的代谢靶点，以增加CD8细胞反应和改善癌症免疫治疗 功效