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，例如原子弹队列，已证明功能障碍和 T 细胞受到干扰 辐射对 T 细胞群产生可测量的急性影响，甚至在暴露几十年后仍能保持稳态。 体内和体外均观察到激活和激活，对 T 细胞的长期生理影响 急性辐射综合症幸存者的免疫力和免疫功能障碍介导的多器官损伤， 以及潜在的机制，仍然存在相当大的不确定性，我们使用细菌感染模型。 最近观察到，在 IR 几个月后，受照射小鼠的病原体负荷更高。 将这种受损的针对病原体的保护性免疫力与受损的 T 细胞免疫力联系起来，我们 报道了异常的免疫代谢重编程和特定代谢途径的扰动 随着人们对新陈代谢和免疫细胞之间相互作用的日益认识，IR 后 T 细胞被激活。 功能，人们越来越认识到幼稚 T 细胞、效应 T 细胞和记忆 T 细胞的不同代谢需求 IR 后需要适当的代谢重编程来维持有效的 T 细胞免疫。 剖析 T 细胞在不同激活/分化阶段的代谢扰动，因为它们有助于 细菌感染小鼠模型将用于评估 IR 对病原体的长期影响。 生理背景下 T 细胞免疫的变化 我们将在本研究中关注 CD8+ T 细胞，因为 CD8+。 亚群对 IR 引起的损伤比 CD4+ 更敏感，其次，它们对于免疫至关重要 除了改变 T 细胞外，还可以防御细胞内病原体，包括病毒和细菌。 代谢方面，我们预计 IR 还会引起明显的全身代谢变化，包括淋巴系统的代谢变化 正如我们发表的代谢组学研究所示，促炎代谢物可能会影响组织和粘膜生态位。 与红外线诱导的过早衰老协同作用并驱动正反馈循环，从而导致多器官 在这个项目中，我们将研究衰老相关炎症表型对 T 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 因此，我们将研究混合中子/光子辐射对 T 的后期影响。 我们还计划解决放射缓解剂如何调节那些由红外线引起的长期代谢的问题。 包括 senolytic 方法在内的持久效果将有助于更好地实现这些目标。 辐射如何导致 ARS 幸存者持续性免疫功能障碍。 T 细胞在特定激活/分化阶段的代谢扰动，例如幼稚 T 细胞与记忆 T 细胞，将 为预防性干预策略奠定基础。