Enforced expression of Spi-B reverses T lineage commitment and blocks beta-selection.
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.
Lefebvre
Juliette M
JM
Immunobiology Working Group, Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Haks
Mariëlle C
MC
Carleton
Michael O
MO
Rhodes
Michele
M
Sinnathamby
Gomathinayagam
G
Simon
M Celeste
MC
Eisenlohr
Laurence C
LC
Garrett-Sinha
Lee Ann
LA
Wiest
David L
DL
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D047109:Fetal Development / Q000235:genetics / Q000276:immunology; D019674:Genes, T-Cell Receptor beta / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013945:Thymoma / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013953:Thymus Neoplasms / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D014161:Transduction, Genetic; D000099232:Proto-Oncogene Protein Spi-1
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C112442:Ehf protein, mouse; C076877:SPIB protein, human