p53-dependent and p53-independent pathways for radiation-induced immature thymocyte differentiation.
The pre-T-cell receptor (TCR) delivers essential survival/differentiation signals to the developing thymocytes. Severe combined immunodeficient (SCID) and recombination-activating gene (RAG)-deficient mice are unable to assemble antigen receptor genes, and therefore cannot express a pre-TCR. Consequently, T lymphocyte differentiation is arrested at an early stage in the thymus of these animals, and immature thymocytes are eliminated through apoptotic processes. This maturation arrest can be relieved and thymocyte differentiation rescued after the exposure of these mice to whole-body gamma-irradiation. Whereas the promotion of immature thymocyte survival/differentiation was shown to require p53 activity in irradiated SCID mice, it was suggested, on the other hand, that p53 activation prevents immature thymocytes survival/differentiation in irradiated RAG-deficient mice. However, SCID mice have impaired responses to ionizing radiation. In this paper, we analysed p53 requirement in radiation-induced thymocyte differentiation in CD3epsilon(Delta5/Delta5) mice, where pre-TCR deficiency also results in an early block of lymphocyte development. Our results show at the cellular and molecular levels that, in this DNA repair-proficient model, irradiation-induced thymocyte differentiation proceeds either by a p53-dependent or by a p53-independent pathway, which differ in their sensitivity to the radiation dose delivered.
Candéias
Serge Michel
SM
1Laboratoire d'Immunochimie, Commissariat à l'Energie Atomique-Grenoble, Département Réponse et Dynamique Cellulaire, INSERM U548, Université Joseph Fourier, 17 rue des martyrs, 38054 Grenoble, France. immuno@dsvsud.cea.fr
Mancini
Stéphane Jean Charles
SJ
Touvrey
Cédric
C
Borel
Eve
E
Jouvin-Marche
Evelyne
E
Marche
Patrice Noël
PN
D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000528:radiation effects*; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D011946:Receptors, Antigen / Q000172:deficiency / Q000235:genetics / Q000528:radiation effects; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
D017252:CD3 Complex; D011946:Receptors, Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016159:Tumor Suppressor Protein p53