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Brief Definitive Reports |
Correspondence to: Avinash Bhandoola, Bldg. 10, Rm. 4B36, National Cancer Institute, Bethesda, MD 20892. Tel:301-496-3199 Fax:301-496-0887
Immature CD4+CD8+ thymocytes rearrange their T cell receptor (TCR)-
gene locus to generate clonotypic /ß TCR, after which a few cells expressing selectable TCR are signaled to further differentiate into mature T cells. Because of requirements for self-tolerance, immature CD4+CD8+ thymocytes are programmed to die in the thymus in response to a variety of stimuli that do not induce death of mature T cells. We now demonstrate that, in contrast to all previously described stimuli, immature CD4+CD8+ thymocytes are selectively more resistant than mature T cells to apoptotic death induced by DNA intercalating agents. Importantly, we demonstrate that DNA intercalating agents induce double-stranded DNA breaks in both immature thymocytes and mature T cells, but immature thymocytes tolerate these DNA breaks, whereas mature T cells are signaled to die by an Atm-dependent but p53-independent death mechanism. Thus, our results indicate that absence of an Atm-dependent but p53-independent pathway allows immature thymocytes to survive double-stranded DNA breaks. It is likely that the unique ability of immature thymocytes to survive DNA-damaging intercalating agents reflects their tolerance of double-stranded DNA breaks that occur normally during antigen receptor gene rearrangements.
Key Words: DNA damage, apoptosis, thymic development, actinomycin D, rearrangement
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