The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses

Immunity. 2007 Sep;27(3):425-37. doi: 10.1016/j.immuni.2007.07.015. Epub 2007 Aug 23.


The molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45RO, or with mutant PTPase null or PTPase-low CD45R0. Whereas CD45 PTPase activity was absolutely required for the reconstitution of thymic development, only 3% of wild-type CD45 activity restored T cell numbers and normal cytotoxic T cell responses. Lowering the CD45 expression increased CD4 lineage commitment. Peripheral T cells with very low activity of CD45 phosphatase displayed reduced TCR signaling, whereas intermediate activity caused hyperactivation of CD4+ and CD8+ T cells. These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology
  • Flow Cytometry
  • Leukocyte Common Antigens / immunology*
  • Lymphocyte Activation / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology*
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Protein Isoforms / immunology
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*


  • Protein Isoforms
  • Receptors, Antigen, T-Cell
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Leukocyte Common Antigens
  • Ptprc protein, mouse