The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate

Nature. 2000 Mar 30;404(6777):506-10. doi: 10.1038/35006664.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD4 Antigens
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8 Antigens
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Lineage*
  • Cells, Cultured
  • Female
  • Lectins, C-Type
  • Leukopoiesis / physiology*
  • Ligands
  • Major Histocompatibility Complex
  • Male
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Immunological
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Cell Surface*
  • Signal Transduction*
  • Thymus Gland / cytology
  • Time Factors
  • Transcription Factors*


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD4 Antigens
  • CD69 antigen
  • CD8 Antigens
  • Lectins, C-Type
  • Ligands
  • Membrane Proteins
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface
  • Transcription Factors