CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse

Nat Immunol. 2004 Aug;5(8):791-9. doi: 10.1038/ni1095. Epub 2004 Jul 11.


How T cells respond with extraordinary sensitivity to minute amounts of agonist peptide and major histocompatibility complex (pMHC) molecules on the surface of antigen-presenting cells bearing large numbers of endogenous pMHC molecules is not understood. Here we present evidence that CD4 affects the responsiveness of T helper cells by controlling spatial localization of the tyrosine kinase Lck in the synapse. This finding, as well as further in silico and in vitro experiments, led us to develop a molecular model in which endogenous and agonist pMHC molecules act cooperatively to amplify T cell receptor signaling. At the same time, activation due to endogenous pMHC molecules alone is inhibited. A key feature is that the binding of agonist pMHC molecules to the T cell receptor results in CD4-mediated spatial localization of Lck, which in turn enables endogenous pMHC molecules to trigger many T cell receptors. We also discuss broader implications for T cell biology, including thymic selection, diversity of the repertoire of self pMHC molecules and serial triggering.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigens / immunology
  • CD4 Antigens / immunology*
  • Computer Simulation
  • Image Processing, Computer-Assisted
  • Lymphocyte Activation / immunology*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology*
  • Major Histocompatibility Complex
  • Mice
  • Models, Immunological*
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / immunology*
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology*


  • Antigens
  • CD4 Antigens
  • Receptors, Antigen, T-Cell
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)