Metabolic impairment plays a critical role in radiation-induced T cell immune dysfunction

代谢损伤在辐射诱导的 T 细胞免疫功能障碍中起着关键作用

• 批准号: 10668368
• 负责人: Albert J Fornace
• 金额: $ 56.89万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668368
• 关键词: Ablation; Acceleration; Acute; Address; Adverse effects; Affect; Animals; Antigens; Bacteria; Bacterial Infections; Biological; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Aging; Cell physiology; Cells; Cellular Metabolic Process; Cellular Structures; Data; Dose; Energy Metabolism; Event; Excision; Exposure to; Feedback; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Glycolysis; Homeostasis; Immune; Immune System Diseases; Immune system; Immunity; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Intervention; Ionizing radiation; Late Effects; Life; Listeria monocytogenes; Lymphoid; Lymphoid Tissue; Measurable; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mucous Membrane; Mus; Neutrons; Nuclear Accidents; Pathway interactions; Phenotype; Photons; Physiological; Play; Population; Positioning Attribute; Prevention strategy; Process; Publications; Publishing; Radiation; Radiation Toxicity; Radiation exposure; Regulation; Reporting; Role; Serum; Signal Transduction; Spleen; Survivors; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Tissues; Uncertainty; Virus; amino acid metabolism; atomic bomb; cohort; epidemiologic data; fatty acid oxidation; immune function; immunosenescence; in vivo; irradiation; lipidomics; metabolomics; mouse model; multiorgan injury; pathogen; pharmacologic; premature; prevent; preventive intervention; radiation effect; radiation mitigator; radioresistant; response; senescence; small molecule; synergism

Abstract The immune system, especially the T cell component, is particularly sensitive to ionization radiation (IR), and epidemiologic data, such as the A-bomb cohort, have demonstrated dysfunction and perturbed T cell homeostasis even decades after exposure. While measurable acute effects of radiation on T cell populations and activation have been observed in vivo and in vitro, the long-term physiologic consequences on T cell immunity in acute-radiation-syndrome survivors and multi-organ injury mediated by immune dysfunction, as well as the underlying mechanisms, still have considerable uncertainty. Using a bacterial infection model, we have recently observed that the pathogen loads were higher in the irradiated mice at months after IR. We can connect this compromised protective immunity against pathogens with impaired T cell immunity, where we have reported abnormal immune metabolic reprogramming and perturbations in specific metabolic pathways in activated T cells after IR. With the growing appreciation of interactions between metabolism and immune cell function, it is increasingly appreciated that distinct metabolic needs in naïve, effector, and memory T cells require proper metabolic reprogramming to maintain effective T cell immunity after IR. One aim will be to dissect metabolic perturbations in T cells in various activation/differentiation stages as they contribute to pathogen immunity. A bacterial infection murine model will be used to assess the long-lasting effects of IR on changes on T cell immunity in a physiologic context. We will focus on CD8+ T cells in this study, because CD8+ subpopulations are more sensitive to IR-caused damage than CD4+, and secondly, they are critical for immune defense against intracellular pathogens, including viruses and bacteria. In addition to altering T cell metabolism, we expect that IR also induces distinct systemic metabolic changes, including those in lymphoid tissue and mucosal niche, as shown in our published metabolomic studies. Pro-inflammatory metabolites may synergize with IR-induced premature senescence and drive a positive feedback loop resulting in multi-organ injury. In this project we will examine the impact of the senescence-associated inflammatory phenotype on T cell metabolism and immune functions, and assess interventions using senescent cell ablation approach. Considering that in a real-life nuclear incident, an exposure to mixed fields of neutrons and photon is highly likely, we have already observed distinct differences between mixed field metabolic responses compared to single photon or neutron beams. So we will investigate the late effects of mixed neutron/photon radiation on T cells’ metabolism. We also plan to address the question how a radiomitigator modulates those IR-caused long- lasting effects including a senolytic approach. The successful completion of these aims will help to better understand how radiation causes persistent immune dysfunction in ARS survivors. The new concept of metabolic perturbations of T cells in specific activation/differentiation stages, e.g., naïve vs memory T cells, will lay the foundation for strategies for preventative intervention.

抽象的 免疫系统，尤其是T细胞成分，对电离辐射（IR）特别敏感，并且 流行病学数据，例如A-BOMB队列，已显示出功能障碍和扰动的T细胞 稳态甚至几十年后。而辐射对T细胞种群的可测量急性影响 在体内和体外观察到激活，对T细胞的长期生理后果 免疫功能障碍介导的急性辐射综合征生存和多器官损伤的免疫力，如 以及基本机制，仍然存在相当大的不确定性。使用细菌感染模型，我们 最近观察到，在IR后几个月，辐照小鼠的病原体负荷较高。我们可以 通过受损的T细胞免疫学连接这种受损害的受保护的免疫学对病原体的影响，我们 已经报道了在特定代谢途径中的异常免疫代谢重编程和扰动 IR后激活的T细胞。随着新陈代谢与免疫细胞之间相互作用的浓缩 功能，越来越多地认为，幼稚，效应子和记忆T细胞中的明显代谢需求 需要适当的代谢重编程以维持IR后有效的T细胞免疫。一个目标是 在各种激活/分化阶段，在T细胞中剖析T细胞的代谢扰动，它们有助于 病原体免疫。细菌感染鼠模型将用于评估IR对IR的长期影响 在生理环境下T细胞免疫的变化。在这项研究中，我们将重点关注CD8+ T细胞，因为CD8+ 与CD4+相比，亚群对IR引起的损害更敏感，其次，它们对于免疫至关重要 防御细胞内病原体，包括病毒和细菌。除了改变T细胞 代谢，我们期望IR还会影响明显的全身代谢变化，包括淋巴机的变化 如我们已发表的代谢组学研究所示，组织和粘膜生态位。促炎性代谢物可能 与IR诱导的过早感应协同作用，并驱动正反馈环，导致多器官 在这个项目中，我们将检查与感应相关的炎症表型对T的影响 细胞代谢和免疫功能，以及使用感觉细胞消融方法进行评估干预措施。 考虑到在现实生活中的核事件中，对中子和光子混合场的暴露是高度的 可能，我们已经观察到混合场代谢反应之间的明显差异与 单光子或中子束。因此，我们将研究混合中子/光子辐射对T的后期影响 细胞的代谢。我们还计划解决一个问题，即放射线仪如何调节IR造成的长期的辐射仪 持久的效果，包括鼻溶剂方法。这些目标的成功完成将有助于改善 了解辐射如何导致ARS表面上的持续免疫功能障碍。新的概念 在特定的激活/分化阶段，T细胞的代谢扰动，例如，幼稚与记忆T细胞将 为预防干预策略奠定基础。