title: The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses.
abstract: 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.
authors: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
authors: Louise
authors: L
authors: McNeill
authors: Robert J
authors: RJ
authors: Salmond
authors: Joanne C
authors: JC
authors: Cooper
authors: Céline K
authors: CK
authors: Carret
authors: Robin L
authors: RL
authors: Cassady-Cain
authors: Marta
authors: M
authors: Roche-Molina
authors: Panna
authors: P
authors: Tandon
authors: Nick
authors: N
authors: Holmes
authors: Denis R
authors: DR
authors: Alexander
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D020033:Protein Isoforms / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse