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.
Modulation of metabolism of T cells within the immune system is emerging as an alternative strategy to increase the strength of immune response to vaccination against infectious diseases, as well as for immunotherapy against cancer. Mitochondria are the engine of the cells that generate energy for many cell processes, and we have recently identified MCJ as a brake for the mitochondrial function in CD8 T cells. In this proposal, we investigate 1) the role of MCJ in human CD8 T cell metabolism and function, and 2) strategies to disrupt MCJ to enhance efficacy of anti-cancer immunotherapy.
