Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD4-Positive T-Lymphocytes / cytology*
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CD4-Positive T-Lymphocytes / immunology
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CD5 Antigens / metabolism
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CD8-Positive T-Lymphocytes / cytology*
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CD8-Positive T-Lymphocytes / immunology
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Cell Differentiation*
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Gene Expression Regulation
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / metabolism
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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Humans
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Jurkat Cells
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Lectins, C-Type
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Liver / cytology
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Liver / embryology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Transgenic
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NFATC Transcription Factors
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Nuclear Proteins*
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Promoter Regions, Genetic / genetics
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Receptor, Notch1
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, Cell Surface*
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Response Elements / genetics
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Signal Transduction
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD5 Antigens
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CD69 antigen
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DNA-Binding Proteins
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Histocompatibility Antigens Class I
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Histocompatibility Antigens Class II
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Lectins, C-Type
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Membrane Proteins
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NFATC Transcription Factors
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NOTCH1 protein, human
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Notch1 protein, mouse
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Nuclear Proteins
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Receptor, Notch1
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Receptors, Antigen, T-Cell
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Receptors, Cell Surface
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Transcription Factor AP-1
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Transcription Factors