Abstract
The molecular changes that restrict multipotent murine thymocytes to the T cell lineage and render them responsive to Ag receptor signals remain poorly understood. In this study, we report our analysis of the role of the Ets transcription factor, Spi-B, in this process. Spi-B expression is acutely induced coincident with T cell lineage commitment at the CD4(-)CD8(-)CD44(-)CD25(+) (DN3) stage of thymocyte development and is then down-regulated as thymocytes respond to pre-TCR signals and develop beyond the beta-selection checkpoint to the CD4(-)CD8(-)CD44(-)CD25(-) (DN4) stage. We found that dysregulation of Spi-B expression in DN3 thymocytes resulted in a dose-dependent perturbation of thymocyte development. Indeed, DN3 thymocytes expressing approximately five times the endogenous level of Spi-B were arrested at the beta-selection checkpoint, due to impaired induction of Egr proteins, which are important molecular effectors of the beta-selection checkpoint. T lineage-committed DN3 thymocytes expressing even higher levels of Spi-B were diverted to the dendritic cell lineage. Thus, we demonstrate that the prescribed modulation of Spi-B expression is important for T lineage commitment and differentiation beyond the beta-selection checkpoint; and we provide insight into the mechanism underlying perturbation of development when that expression pattern is disrupted.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation / genetics*
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Cell Differentiation / immunology*
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Cell Line, Tumor
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Cell Lineage / genetics
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Cell Lineage / immunology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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Dendritic Cells / cytology
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Dendritic Cells / immunology
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Fetal Development / genetics
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Fetal Development / immunology
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Genes, T-Cell Receptor beta / immunology*
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Organ Culture Techniques
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics*
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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Thymoma / genetics
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Thymoma / immunology
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Thymus Neoplasms / genetics
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Thymus Neoplasms / immunology
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Trans-Activators / biosynthesis*
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Trans-Activators / deficiency
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Trans-Activators / genetics*
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transduction, Genetic
Substances
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DNA-Binding Proteins
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Ehf protein, mouse
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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proto-oncogene protein Spi-1
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SPIB protein, human