Differential Radiosensitivity in T-Cell Subsets: Metabolic and Antioxidative Mechanisms Underlying Naïve T-Cell...

T cells, which are generally highly sensitive to DNA damage-induced cell death, exhibit distinct responses to ionizing radiation (IR) depending on their differentiation state. In this study, we investigated the heightened radiosensitivity of naïve T cells (Tn) compared to memory T cells (Tm) through in vivo and in vitro models. Following whole-body irradiation (WBI), naïve T cells, particularly naïve CD8+ T cells, displayed significant depletion and delayed recovery, compared to their Tm counterparts. Transcriptomic analyses revealed similar p53 pathway activation in both Tn and Tm postirradiation but highlighted key differences in cytokine signaling and metabolic profiles between these two cell states. Tm cells showed elevated expression of survival-promoting cytokine receptors, anti-apoptotic genes, and mitochondrial respiratory activity, coupled with robust antioxidative defense systems, including increased glutathione synthesis and thioredoxin reductase activity. Supplementation with N-acetylcysteine, a reactive oxygen species (ROS) scavenger, partially mitigated Tn depletion after WBI, underscoring the role of oxidative stress in Tn radiosensitivity. These findings suggest that the metabolic and antioxidative adaptations of Tm confer greater intrinsic resilience against radiation-induced damage than those of Tn. This disparity underscores the importance of targeted interventions to preserve naïve T cell populations and maintain immune balance after radiation exposure.