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

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，已经显示出功能障碍和T细胞紊乱 即使在暴露几十年后，动态平衡也是如此。虽然辐射对T细胞群的急性影响是可测量的 并在体内和体外观察到了T细胞的长期生理后果 急性放射综合征幸存者的免疫功能及免疫功能紊乱所致的多器官损伤 以及潜在的机制，仍然存在相当大的不确定性。使用细菌感染模型，我们 最近观察到，在IR后的几个月里，受照射的小鼠的病原体载量更高。我们可以的 将这种对病原体的保护性免疫受损与T细胞免疫受损联系起来，在那里我们 已经报告了免疫代谢重新编程异常和特定代谢途径的干扰 IR后T细胞活化。随着对新陈代谢和免疫细胞之间相互作用的认识日益加深 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新编程以维持有效的T细胞免疫。一个目标将是 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 病原体免疫。细菌感染小鼠模型将被用来评估IR对 T细胞免疫在生理环境中的变化。在这项研究中，我们将重点关注CD8+T细胞，因为CD8+ 亚群对红外线引起的损伤比CD4+更敏感，其次，他们对免疫至关重要 防御细胞内病原体，包括病毒和细菌。除了改变T细胞外 新陈代谢，我们预计IR也会引起明显的全身新陈代谢变化，包括淋巴组织的变化 组织和粘膜生态位，正如我们发表的代谢组学研究所显示的那样。促炎代谢物可能 协同IR诱导的早衰，并驱动正反馈循环，导致多器官 受伤。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，暴露在中子和光子混合场中的几率很高 很可能，我们已经观察到混合现场代谢反应与 单光子或中子束。因此，我们将研究中子/光子混合辐射对T的后期效应 细胞新陈代谢。我们还计划解决这样一个问题，即放射增强器如何调制那些由IR引起的长期辐射- 持久的影响，包括分解感官的方法。这些目标的成功实现将有助于更好地 了解辐射如何导致ARS幸存者的持续性免疫功能障碍。新概念-- T细胞在特定激活/分化阶段的代谢扰动，例如，幼稚T细胞与记忆性T细胞 为预防性干预战略奠定基础。

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.