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 β-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 β-selection checkpoint, due to impaired induction of Egr proteins, which are important molecular effectors of the β-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 β-selection checkpoint; and we provide insight into the mechanism underlying perturbation of development when that expression pattern is disrupted.
Original language | English |
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Pages (from-to) | 6184-6194 |
Number of pages | 11 |
Journal | Journal of Immunology |
Volume | 174 |
Issue number | 10 |
DOIs | |
State | Published - May 15 2005 |
Keywords
- Animals
- Cell Differentiation/genetics
- Cell Line, Tumor
- Cell Lineage/genetics
- DNA-Binding Proteins/biosynthesis
- Dendritic Cells/cytology
- Down-Regulation/genetics
- Fetal Development/genetics
- Genes, T-Cell Receptor beta/immunology
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, SCID
- Organ Culture Techniques
- Proto-Oncogene Proteins/biosynthesis
- T-Lymphocyte Subsets/cytology
- Thymoma/genetics
- Thymus Gland/cytology
- Thymus Neoplasms/genetics
- Trans-Activators/biosynthesis
- Transcription Factors/biosynthesis
- Transduction, Genetic