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.

摘要 免疫系统，特别是T细胞成分，对电离辐射（IR）特别敏感， 流行病学数据，如原子弹队列，已经证明功能障碍和干扰T细胞， 甚至几十年后的体内平衡。虽然辐射对T细胞群的可测量的急性影响 在体内和体外都观察到了激活，对T细胞的长期生理后果 急性辐射综合征幸存者的免疫和免疫功能障碍介导的多器官损伤， 以及其背后的机制，仍然有相当大的不确定性。使用细菌感染模型，我们 最近观察到，在IR后几个月，受照射小鼠的病原体负荷较高。 将这种针对病原体的保护性免疫力受损与T细胞免疫力受损联系起来，我们 已经报道了异常的免疫代谢重编程和特定代谢途径的干扰， 随着人们对代谢和免疫细胞之间相互作用的认识不断加深， 功能，越来越多的人认识到，幼稚，效应和记忆T细胞的不同代谢需求 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 剖析T细胞在不同活化/分化阶段的代谢扰动，因为它们有助于 病原体免疫将使用细菌感染小鼠模型来评估IR对以下的长期作用： 在生理环境中T细胞免疫的变化。在这项研究中，我们将重点关注CD 8 + T细胞，因为CD 8 + T细胞是一种免疫调节细胞。 亚群对IR引起的损伤比CD 4+更敏感，其次，它们对免疫功能的恢复至关重要。 防御细胞内病原体，包括病毒和细菌。除了改变T细胞 因此，我们认为IR还诱导了不同的全身代谢变化，包括淋巴细胞的代谢变化。 组织和粘膜生态位，如我们发表的代谢组学研究所示。促炎代谢物可能 与IR诱导过早衰老协同作用并驱动正反馈回路，导致多器官 损伤在这个项目中，我们将研究衰老相关的炎症表型对T细胞的影响。 细胞代谢和免疫功能，并使用衰老细胞消融方法评估干预措施。 考虑到在现实生活中的核事件中，暴露于中子和光子的混合场是高度危险的。 很可能，我们已经观察到混合场代谢反应与 单光子或中子束。因此，我们将研究中子/光子混合辐射对T 细胞的新陈代谢。我们还计划解决一个问题，即辐射调节剂如何调节这些红外线引起的长期- 持久的影响，包括衰老的方法。这些目标的顺利实现将有助于更好地 了解辐射如何导致ARS幸存者的持续免疫功能障碍。新理念 T细胞在特定活化/分化阶段的代谢扰动，例如，幼稚T细胞与记忆T细胞， 为预防性干预战略奠定基础。