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Metabolic alterations in age-associated dendritic cell dysfunction

与年龄相关的树突状细胞功能障碍的代谢改变

基本信息

批准号：
9311155
负责人：
CLAIRE A CHOUGNET
金额：
$ 50.78万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311155
关键词：
Affect Age Aging Antigen Presentation Antigen-Presenting Cells Antigens B-Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Carbon Cell physiology Cells Cellular biology Communicable Diseases Consumption Coupling Cross Presentation Cross-Priming Cytomegalovirus Data Defect Dendritic Cells Dependence Effector Cell Elderly Elements Environment Exhibits Functional disorder Genetic Genus Hippocampus Histocompatibility Antigens Class I Human Immune System Diseases Immune System and Related Disorders Immune response Impairment In Vitro Influenza Knowledge Liposomes MHC Class I Genes Macaca Malignant Neoplasms Mammals Membrane Potentials Memory Metabolic Metabolic Pathway Mitochondria Modeling Mus NADH Oxidative Phosphorylation Peptides Phagocytes Phagocytosis Pharmacology Phenotype Population Predisposition Process Production Protons Publishing Radio Series Source T cell response T-Lymphocyte Testing Therapeutic Time Tracer Transgenic Organisms UCP2 protein Viral age effect age related aged base cytokine experimental study improved in vivo in vivo Model metabolic phenotype mitochondrial dysfunction mitochondrial fitness mouse model novel novel therapeutics pathogen response tumor

项目摘要

Aging is associated with progressive immune dysfunction, resulting in blunted effector responses and increased susceptibility to infectious disease and cancers. A significant contributor to this decreased responsiveness is the impaired functionality of the most potent Ag-presenting cells, the dendritic cells (DCs). A key aspect of DC function is their capacity to “cross-present” cell-associated Ag to CD8+T cells, a process that is required to cross-prime CD8+T cell responses against tumors or intra-cellular pathogens. However, the effect of aging on the acquisition, processing, and presentation of cell-associated Ags by primary DCs has barely been studied. We recently uncovered that aging significantly reduced the cross-presenting and cross-priming capacity of the DC subsets the most efficient at carrying out this important task (CD8αDCs and merocytic DCs). Aged DCs expressed normal MHC class I levels and were able to prime CD8+T cells to soluble peptides, but they were strikingly impaired in terms of phagocytosis of cell-associated materials. Mechanistically, the bio-energetic status, notably mitochondrial activity and membrane potential (Δψm), has been shown to regulate DC phagocytic capacity. Mitochondrial function was profoundly affected in murine CD8α or mcDCs, as shown by lower Δψm, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and ROS production. Old macaque CD1c+ DCs displayed similar defects, demonstrating dysfunction across species. Pharmacologic manipulation of young DCs to mimic the aged metabolic phenotype significantly impeded their phagocytic and cross-priming capacity, but in vitro scavenging of ROS by NAC significantly reversed the cross-presentation defect of aged! DCs. Our inter-related hypotheses are: (1) age-related changes in mitochondrial activity diminish the phagocytic and cross-presenting activity of murine DCs; and (2) improving mitochondrial activity will boost DC functionality and their potential as anti-tumor therapeutics in the elderly. These hypotheses will be tested in the following 3 aims. Aim 1 will identify the mechanisms underlying decreased mitochondrial fitness in aged murine DCs. We will dissect the effect of aging on DC use of, and dependence on, specific carbon sources and metabolic pathways to meet their energy needs. Moreover, we will assess whether the observed metabolic changes result from defects in the DC precursor, the aged environment in which they differentiate, or a combination of both. Aim 2 will determine whether improving mitochondrial activity of aged murine DCs increases their capacity to induce more vigorous T cell responses to cell-associated Ags in vitro, while Aim 3 will study the effect of improving mitochondrial function on their capacity to induce anti-tumor responses using well-established in vivo models of cross-presentation. !

衰老与进行性免疫功能障碍有关，导致效应反应迟钝和