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

SIMPLE SUMMARY: Because children have a long life expectancy relative to adults and their tissues and organs are growing and developing rapidly, the risk of radiation carcinogenesis for children is considered higher than that for adults. However, the underlying mechanism(s) is unclear. To uncover the mechanism, we previously revealed that principal causative genes in mouse thymic lymphomas arising in irradiated infants or adults 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. Our results demonstrate that the dynamics of thymocytes during the post-irradiation period depends on the age at exposure. For irradiated infants in particular, the number of proliferating cells increase dramatically, and this correlate with activation of the PI3K-AKT-mTOR pathway. Thus, we conclude that the PI3K-AKT-mTOR pathway in infants contributed, at least in part, to thymus-cell dynamics through the modification of cell proliferation and survival after irradiation, which may be associated with the risk of Pten mutation-associated thymic lymphoma. 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.