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Cell Growth & Differentiation Vol. 11, 91-98, February 2000
© 2000 American Association for Cancer Research


Articles

A Role for E2F1 in the Induction of Apoptosis during Thymic Negative Selection1

Itxaso García, Matilde Murga, Alberto Vicario, Seth J. Field2 and Ana M. Zubiaga3

Department of Animal Biology and Genetics, Faculty of Sciences, University of the Basque Country, E-48080, Spain [I. G., M. M., A. V., A. M. Z.], and Children’s Hospital, Department of Neuroscience, Harvard Medical School, Boston, Massachusetts 02115 [S. J. F.]

Abstract

Thymic negative selection is the process in which maturing thymocytes that express T-cell receptors recognizing self are eliminated by apoptotic cell death. The molecular mechanism by which this occurs is poorly understood. Notably, genes involved in cell death, even thymocyte death, such as Fas, Fas-ligand, p53, caspase-1, caspase-3, and caspase-9, and Bcl-2 have been found to not be required for normal thymic negative selection. We have demonstrated previously that E2F1-deficient mice have a defect in thymocyte apoptosis. Here we show that E2F1 is required for normal thymic negative selection. Furthermore, we observed an E2F1-dependent increase of p53 protein levels during the process of thymic clonal deletion, which suggests that E2F1 regulates activation-induced apoptosis of self-reactive thymocytes by a p53-dependent mechanism. In contrast, other apoptotic pathways operating on developing thymocytes, such as glucocorticoid-induced cell death, are not mediated by E2F1. The T lymphocytes that escape thymic negative selection migrate to the peripheral immune system but do not appear to be autoreactive, indicating that there may exist E2F1-independent mechanisms of peripheral tolerance, which protect mice from developing an autoimmune response. We expect that E2F1-deficient mice will provide a useful tool for understanding the molecular mechanism of and the immunological importance of thymic negative selection.




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