title: The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate.
abstract: Signals elicited by binding of the T-cell antigen receptor and the CD4/CD8 co-receptor to major histocompatibility complex (MHC) molecules control the generation of CD4+ (helper) or CD8+ (cytotoxic) T cells from thymic precursors that initially express both co-receptor proteins. These precursors have unique, clonally distributed T-cell receptors with unpredictable specificity for the self-MHC molecules involved in this differentiation process. However, the mature T cells that emerge express only the CD4 (MHC class II-binding) or CD8 (MHC class I-binding) co-receptor that complements the MHC class-specificity of the T-cell receptor. How this matching of co-receptor-defined lineage and T-cell-receptor specificity is achieved remains unknown, as does whether signalling by the T-cell receptors, co-receptors and/or general cell-fate regulators such as Notch-1 contributes to initial lineage choice, to subsequent differentiation processes or to both. Here we show that the CD4 versus CD8 lineage fate of immature thymocytes is controlled by the co-receptor-influenced duration of initial T-cell receptor-dependent signalling. Notch-1 does not appear to be essential for this fate determination, but it is selectively required for CD8+ T-cell maturation after commitment directed by T-cell receptors. This indicates that the signals constraining CD4 versus CD8 lineage decisions are distinct from those that support subsequent differentiation events such as silencing of co-receptor loci.
authors.affiliation: Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yasutomo
authors.forename: C
authors.initials: C
authors.lastname: Doyle
authors.forename: L
authors.initials: L
authors.lastname: Miele
authors.forename: C
authors.initials: C
authors.lastname: Fuchs
authors.forename: R N
authors.initials: RN
authors.lastname: Germain
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D016827:CD8 Antigens; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D019070:Cell Lineage; D002478:Cells, Cultured; D005260:Female; D037181:Lectins, C-Type; D019891:Leukopoiesis / Q000502:physiology*; D008024:Ligands; D008285:Major Histocompatibility Complex; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000099192:CD69 Antigens; C497762:Notch1 protein, mouse