The Differential Regulation of Lck Kinase Phosphorylation Sites by CD45 Is Critical for T Cell Receptor Signaling Responses

• Published in: Immunity (Cambridge, Mass.) Mass.), 2007-09, Vol.27 (3), p.425-437
• Main Authors: McNeill, Louise, Salmond, Robert J., Cooper, Joanne C., Carret, Céline K., Cassady-Cain, Robin L., Roche-Molina, Marta, Tandon, Panna, Holmes, Nick, Alexander, Denis R.
• Format: Article
• Language: English
• Subjects: Animals; Biotechnology; Cell Differentiation - immunology; CELLIMMUNO; Cloning; Flow Cytometry; Kinases; Leukocyte Common Antigens - immunology; Lymphocyte Activation - immunology; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - immunology; Lymphocytes; Mice; Mice, Transgenic; MOLIMMUNO; Mutation; Phosphorylation; Protein Isoforms - immunology; Proteins; Receptors, Antigen, T-Cell - immunology; Regulation; Rodents; Signal Transduction - immunology; Software; Statistical methods; T cell receptors; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Technological change
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.07.015

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.