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p53-dependent and p53-independent pathways for radiation-induced immature thymocyte differentiation

Oncogene volume 23, pages 1922–1929 (2004)Cite this article

Abstract

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 γ-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 CD3ɛΔ5/Δ5 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.

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Abbreviations

SCID:

severe combined immune deficiency

RAG:

recombination-activating gene

IR:

ionizing radiation

TCR:

T-cell receptor

DN:

double negative

DP:

double positive

SP:

single positive

Gy:

gray

wt:

wild type

DNA-PKcs:

catalytic subunit of the protein kinase activated by DNA

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Acknowledgements

We thank Véronique Collin for assistance with FACS analysis, Irène Maréchal and Nicolas Chaumontel for animal care and Drs R Ceredig, HR McDonald and C Viret for the critical reading of the manuscript. This work was supported by institutional grants from the ‘Institut National de la Santé et de la Recherche Médicale’, the ‘Commissariat à l'Energie Atomique’ and the Joseph Fourier University, and by a specific action (‘Thématiques Prioritaires’) from the ‘Région Rhône-Alpes. SJCM was supported by grants from the ‘Ministère de l'Education Nationale, de la Recherche et de la Technologie’ and from ‘La Ligue Nationale pour la Recherche contre le Cancer’.

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  1. Stéphane Jean Charles Mancini

    Present address: Ludwig Institute for Cancer research, Chemin des Boveresses 155, 1066, Epalinges, Switzerland

Authors and Affiliations

  1. Département Réponse et Dynamique Cellulaire, Laboratoire d'Immunochimie, Commissariat à l'Energie Atomique-Grenoble, INSERM U548, Université Joseph Fourier, 17 rue des martyrs, Grenoble, 38054, France

    Serge Michel Candéias, Stéphane Jean Charles Mancini, Cédric Touvrey, Eve Borel, Evelyne Jouvin-Marche & Patrice Noël Marche

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  1. Serge Michel Candéias
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Correspondence to Serge Michel Candéias.

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Candéias, S., Mancini, S., Touvrey, C. et al. p53-dependent and p53-independent pathways for radiation-induced immature thymocyte differentiation. Oncogene 23, 1922–1929 (2004). https://doi.org/10.1038/sj.onc.1207320

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