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Izon, DJ, Punt, JA, Xu, L, Karnell, FG, Allman, D, Myung, PS, Boerth, NJ, Pui, JC, Koretzky, GA and Pear, WS (2001) Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength. Immunity 14:253-64
Notch signaling regulates cell fate decisions in multiple lineages. We demonstrate in this report that retroviral expression of activated Notch1 in mouse thymocytes abrogates differentiation of immature CD4+CD8+ thymocytes into both CD4 and CD8 mature single-positive T cells. The ability of Notch1 to inhibit T cell development was observed in vitro and in vivo with both normal and TCR transgenic thymocytes. Notch1-mediated developmental arrest was dose dependent and was associated with impaired thymocyte responses to TCR stimulation. Notch1 also inhibited TCR-mediated signaling in Jurkat T cells. These data indicate that constitutively active Notch1 abrogates CD4+ and CD8+ maturation by interfering with TCR signal strength and provide an explanation for the physiological regulation of Notch expression during thymocyte development.
Animals; Antigens, CD/metabolism; Antigens, CD5/metabolism; Antigens, Differentiation, T-Lymphocyte/metabolism; CD4-Positive T-Lymphocytes/cytology; CD4-Positive T-Lymphocytes/immunology; CD8-Positive T-Lymphocytes/cytology; CD8-Positive T-Lymphocytes/immunology; Cell Differentiation; DNA-Binding Proteins/metabolism; Flow Cytometry; Gene Expression Regulation; Histocompatibility Antigens Class I/immunology; Histocompatibility Antigens Class I/metabolism; Histocompatibility Antigens Class II/immunology; Histocompatibility Antigens Class II/metabolism; Humans; Jurkat Cells; Lectins, C-Type; Liver/cytology; Liver/embryology; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mice, Transgenic; NFATC Transcription Factors; Nuclear Proteins; Promoter Regions, Genetic/genetics; Receptor, Notch1; Receptors, Antigen, T-Cell/genetics; Receptors, Antigen, T-Cell/immunology; Receptors, Antigen, T-Cell/metabolism; Receptors, Cell Surface; Response Elements/genetics; Signal Transduction; Thymus Gland/cytology; Thymus Gland/immunology; Thymus Gland/metabolism; Transcription Factor AP-1/metabolism; Transcription Factors/metabolism
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