Upregulation of CD4 expression during MHC class II-specific positive selection is essential for error-free lineage choice

Immunity. 2009 Sep 18;31(3):480-90. doi: 10.1016/j.immuni.2009.07.006. Epub 2009 Sep 10.


The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete for the identical selecting ligand. CD4 upregulation occurred for endogenously encoded CD4 coreceptors, but CD4 transgenes were downregulated during positive selection, disrupting MHC II-specific TCR signaling and causing lineage errors regardless of the absolute number or signaling strength of transgenic CD4 proteins. Thus, the kinetics of CD4 coreceptor expression during MHC II-specific positive selection determines the integrity of CD4 lineage choice, revealing an elegant symmetry between coreceptor kinetics and lineage choice.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology*
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Lineage*
  • Core Binding Factor Alpha 3 Subunit / metabolism
  • Histocompatibility Antigens Class II / immunology*
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Up-Regulation*


  • CD4 Antigens
  • Core Binding Factor Alpha 3 Subunit
  • Histocompatibility Antigens Class II
  • Ligands
  • Receptors, Antigen, T-Cell
  • Runx3 protein, mouse