Abstract
Signaling through the pre-TCR is essential for early T cell development and is severely impaired in mice lacking the CD3 gamma chain of the pre-TCR. We here address the molecular mechanisms underlying this defect. Impaired pre-TCR signaling is shown to be associated with a profound increase in the number of apoptotic CD4- CD8- (DN) thymocytes. Introduction of p53 deficiency into CD3 gamma-deficient mice completely reverses the cell survival defect in CD3 gamma-deficient DN thymocytes and rescues the block in pre-T cell differentiation. In addition, the CD4+ CD8+ (DP) compartment is expanded to its normal size. These findings suggest that the pre-TCR regulates progression through the DNA-damage checkpoint of the DN to DP transition by inactivating p53.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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CD3 Complex / genetics
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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Mice
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Mice, SCID
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Mice, Transgenic
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Receptors, Antigen, T-Cell / deficiency
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Stem Cells / cytology
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Stem Cells / metabolism*
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Stem Cells / pathology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocyte Subsets / pathology
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Thymus Gland / cytology
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Thymus Gland / pathology
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Transgenes / immunology
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
Substances
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CD3 Complex
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Antigen, T-Cell
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Tumor Suppressor Protein p53