title: Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength.
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.
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
authors: D J
authors: DJ
authors: Izon
authors: J A
authors: JA
authors: Punt
authors: L
authors: L
authors: Xu
authors: F G
authors: FG
authors: Karnell
authors: D
authors: D
authors: Allman
authors: P S
authors: PS
authors: Myung
authors: N J
authors: NJ
authors: Boerth
authors: J C
authors: JC
authors: Pui
authors: G A
authors: GA
authors: Koretzky
authors: W S
authors: WS
authors: Pear
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018956:CD5 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D037181:Lectins, C-Type; D008099:Liver / Q000166:cytology / Q000196:embryology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018956:CD5 Antigens; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D037181:Lectins, C-Type; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099192:CD69 Antigens; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse