Post-Irradiation Thymic Regeneration in B6C3F1 Mice Is Age Dependent and Modulated by Activation of the PI3K-AKT-mTOR Pathway.

ABSTRACT

The risk of radiation-induced carcinogenesis depends on age at exposure. We previously reported principal causative genes in lymphomas arising after infant or adult exposure to 4-fractionated irradiation as Pten or Ikzf1, respectively, suggesting that cells with mutation in these genes might be the origin of lymphomas arising after irradiation depending on age at exposure. Here, we clarified the age-dependent differences in thymus-cell dynamics in mice during the initial post-irradiation period. The thymocyte number initially decreased, followed by two regeneration phases. During the first regeneration, the proportion of phosphorylated-AKT-positive (p-AKT+) cells in cell-cycle phases S+G2/M of immature CD4-CD8- and CD4+CD8+ thymocytes and in phases G0/G1 of mature CD4+CD8- and CD4-CD8+ thymocytes was significantly greater in irradiated infants than in irradiated adults. During the second regeneration, the proportion of p-AKT+ thymocytes in phases G0/G1 increased in each of the three populations other than CD4-CD8- thymocytes more so than during the first regeneration. Finally, PI3K-AKT-mTOR signaling in infants contributed, at least in part, to biphasic thymic regeneration through the modification of cell proliferation and survival after irradiation, which may be associated with the risk of Pten mutation-associated thymic lymphoma.