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

Louise McNeill, Robert J. Salmond, Joanne C Cooper, Celine K Carret, Robin Cassady-Cain, Marta Roche-Molina, Panna Tandon, Nick Holmes, Denis R Alexander

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)425-37
Number of pages13
JournalImmunity
Volume27
Issue number3
Publication statusPublished - Sept 2007

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Antigens, CD45/immunology
  • Cell Differentiation/immunology
  • Flow Cytometry
  • 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

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