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Enforced Expression of Spi-B Reverses T Lineage Commitment and Blocks -Selection ¹

Juliette M. Lefebvre^*, Mariëlle C. Haks^2,*, Michael O. Carleton^3,*, Michele Rhodes^*, Gomathinayagam Sinnathamby, M. Celeste Simon, Laurence C. Eisenlohr, Lee Ann Garrett-Sinha and David L. Wiest^4,*

^* Immunobiology Working Group, Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111; Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107; Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Biochemistry, State University of New York, Buffalo, NY 14214

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 -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 -selection checkpoint, due to impaired induction of Egr proteins, which are important molecular effectors of the -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 -selection checkpoint; and we provide insight into the mechanism underlying perturbation of development when that expression pattern is disrupted.

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