Targeting mitochondrial regulator MCJ to enhance CD8 cell immune response

项目总结 新陈代谢现在被认为是免疫细胞功能的主要调节因素，并影响 免疫反应的进程。研究免疫细胞的新陈代谢变化如何影响 免疫应答正成为免疫学研究的一个重要领域。控制T细胞新陈代谢 作为一种调节免疫反应的替代策略出现，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细胞都经历了重新编程 它们的代谢途径导致作为代谢能量主要来源的三磷酸腺苷的产生。因此，在 目标是通过治疗性增加CD8细胞免疫反应的情况(例如，疫苗， 癌症免疫疗法)，在不影响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式。不幸的是，尚未确定实现这一目标的良好战略。 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)的络合物I的调节剂。MCJ在CD8细胞中大量表达， 相对于其他免疫细胞。我们已经证明，来自MCJ KO小鼠的CD8细胞增加了 线粒体膜电位、线粒体呼吸和线粒体ATP的产生，但正常 糖酵解。此外，线粒体呼吸的增加促进了细胞因子的分泌和细胞毒作用。 活动。由于线粒体的动态特征和在细胞内重新定位的能力，它们是维持 胞质中富含ATP的微区。因此，线粒体来源的ATP有助于维持特定的 高能量的细胞过程(对三磷酸腺苷的高度需求)，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，我们已经证明了MCJ缺陷的CD8细胞具有 超强的防护能力。我们认为，MCJ可能是提高线粒体代谢的靶点。 CD8细胞潜在地增强CD8细胞介导的疫苗和CD8细胞介导的疫苗的效力 免疫疗法。在本申请的上下文中，我们建议解决1)MCJ是否充当 人CD8细胞线粒体内源性刹车，以及干扰MCJ表达是否增加 人CD8细胞产生细胞因子和杀伤靶细胞的能力，2)MCJ的丢失是否可以作为一种 利用小鼠模型改进免疫治疗的策略。拟议的研究结果将使MCJ 成为提高CD8细胞反应和改善癌症免疫治疗的有希望的代谢靶点 功效。

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.