The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses.
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.
McNeill
Louise
L
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
Salmond
Robert J
RJ
Cooper
Joanne C
JC
Carret
Céline K
CK
Cassady-Cain
Robin L
RL
Roche-Molina
Marta
M
Tandon
Panna
P
Holmes
Nick
N
Alexander
Denis R
DR
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*
D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse