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 language | English |
---|---|
Pages (from-to) | 425-37 |
Number of pages | 13 |
Journal | Immunity |
Volume | 27 |
Issue number | 3 |
Publication status | Published - 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