Enforced expression of Spi-B reverses T lineage commitment and blocks β-selection

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

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 languageEnglish
Pages (from-to)6184-6194
Number of pages11
JournalJournal of Immunology
Volume174
Issue number10
DOIs
StatePublished - 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

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