Immature thymocytes undergoing receptor rearrangements are resistant to an Atm-dependent death pathway activated in mature T cells by double-stranded DNA breaks.
Immature CD4(+)CD8(+) thymocytes rearrange their T cell receptor (TCR)-alpha gene locus to generate clonotypic alpha/beta 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.
Bhandoola
A
A
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. bhandooa@exchange.nih.gov
Dolnick
B
B
Fayad
N
N
Nussenzweig
A
A
Singer
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D053222:Fas Ligand Protein; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D019673:Genes, T-Cell Receptor alpha; D006657:Histones / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006657:Histones; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003609:Dactinomycin