Proceedings of the National Academy of Sciences · 2011 · 65 citations · 45 references
Life SciencesDevelopmental BiologyMolecular BiologyCell SignalingDevelopmental ImmunologySignal TransductionRas Family OncogenesT Cell BiologyT Cell DevelopmentT Cell DifferentiationT Cell Receptor SignalingThymic DevelopmentErk SignalingNegative SelectionNegative Selection In ThymocytesPositive SelectionPositive Selection Of T CellsPre-t Cell Receptor SignalingSmall G-protein SignalingThymic T Cell Development
Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre-T-cell receptor (pre-TCR)- but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR-stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development.
45
Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes
Paweł Kisielow, Horst Blüthmann, Uwe D. Staerz et al. · Nature · 1988 · 1.7K citations