Developmental regulation of p53-dependent radiation-induced thymocyte apoptosis in mice.

The production of T cell receptor αβ+ ( TCRαβ+) T lymphocytes in the thymus is a tightly regulated process that can be monitored by the regulated expression of several surface molecules, including CD4, CD8, c Kit, CD25 and the TCR itself, after TCR genes have been assembled from discrete V, D (for TCR-β) and J gene segments by a site-directed genetic recombination. Thymocyte differentiation is the result of a delicate balance between cell death and survival: developing thymocytes die unless they receive a positive signal to proceed to the next stage. This equilibrium is altered in response to various physiological or physical stresses such as ionizing radiation, which induces a massive p53-dependent apoptosis of CD4+ CD8+ double-positive ( DP) thymocytes. Interestingly, these cells are actively rearranging their TCR-α chain genes. To unravel an eventual link between V( D) J recombination activity and thymocyte radio-sensitivity, we analysed the dynamics of thymocyte apoptosis and regeneration following exposure of wild-type and p53-deficient mice to different doses of γ-radiation. p53-dependent radio-sensitivity was already found to be high in immature CD4− CD8− (double-negative, DN) c Kit+ CD25+ thymocytes, where TCR-β gene rearrangement is initiated. However, TCR-αβ− CD8+ immature single-positive thymocytes, an actively cycling intermediate population between the DN and DP stages, are the most radio-sensitive cells in the thymus, even though their apoptosis is only partially p53-dependent. Within the DP population, TCR-αβ+ thymocytes that completed TCR-α gene recombination are more radio-resistant than their TCR-αβ− progenitors. Finally, we found no correlation between p53 activation and thymocyte sensitivity to radiation-induced apoptosis. [ABSTRACT FROM AUTHOR]