Targeting mitochondrial regulator MCJ to enhance CD8 cell immune response
Targeting mitochondrial regulator MCJ to enhance CD8 cell immune response
批准号:
10293952
负责人:
Mercedes Rincon
金额:
$31.64万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-12-01 至 2022-11-30
关键词:
ATP Synthesis PathwayAddressAffectAntigensAreaCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCell physiologyCellsCellular Metabolic ProcessCitric Acid CycleCommunicable DiseasesCytoplasmic GranulesCytosolDoseEngineeringFeedsGenerationsGlucoseGlutamineGlycolysisGlycolysis InhibitionGoalsHumanImmuneImmune responseImmune systemImmunologyImmunotherapyIn VitroInner mitochondrial membraneIntegral Membrane ProteinKnockout MiceLeadMalignant NeoplasmsMediatingMembrane PotentialsMemoryMetabolicMetabolic PathwayMetabolismMethylationMindMitochondriaModelingMusNADH dehydrogenase (ubiquinone)Nonesterified Fatty AcidsNucleotide BiosynthesisOxidative PhosphorylationPathway interactionsProductionProtein DeficiencyProteinsRespirationRoleSourceT-LymphocyteTestingTherapeuticTissuesVaccinationVaccinesViral VaccinesXenograft Modelanti-tumor immune responsearmcancer immunotherapyclinically relevantcontextual factorscytokinecytotoxiccytotoxicityfatty acid oxidationhealthy volunteerimmune functionimprovedin vivoinfluenza infectioninfluenzavirusinterestmetabolic abnormality assessmentmitochondrial membranemitochondrial metabolismmouse modelneoplastic cellnovel strategiesnovel therapeuticsprotein expressionresponsetranslational impact
中文摘要
项目总结
英文摘要
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.
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会议论文
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海外基金