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Lefebvre JM, Haks MC, Carleton MO, Rhodes M, Sinnathamby G, Simon MC, Eisenlohr LC, Garrett-Sinha LA, Wiest DL
Enforced expression of Spi-B reverses T lineage commitment and blocks beta-selection
Journal of Immunology (2005) 174:6184-6194.
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-c ommitted 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.
Note
Publication Date: 2005-05-15.
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Last updated on Wednesday, February 05, 2020