"U54 DK110805"
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Self-non-self discrimination is central to T cell-mediated immunity. The kinetic proofreading model can explain T cell antigen receptor (TCR) ligand discrimination; however, the rate-limiting steps have not been identified. Here, we show that tyrosine phosphorylation of the T cell adapter protein LAT at position Y132 is a critical kinetic bottleneck for ligand discrimination. LAT phosphorylation at Y132, mediated by the kinase ZAP-70, leads to the recruitment and activation of phospholipase C-γ1 (PLC-γ1), an important effector molecule for T cell activation. The slow phosphorylation of Y132, relative to other phosphosites on LAT, is governed by a preceding glycine residue (G131) but can be accelerated by substituting this glycine with aspartate or glutamate. Acceleration of Y132 phosphorylation increases the speed and magnitude of PLC-γ1 activation and enhances T cell sensitivity to weaker stimuli, including weak agonists and self-peptides. These observations suggest that the slow phosphorylation of Y132 acts as a proofreading step to facilitate T cell ligand discrimination.
- MeSH
- adaptorové proteiny signální transdukční imunologie metabolismus MeSH
- aktivace lymfocytů * MeSH
- fosfolipasa C gama metabolismus MeSH
- fosforylace imunologie MeSH
- ligandy MeSH
- membránové proteiny imunologie metabolismus MeSH
- myši MeSH
- protein-tyrosinkináza ZAP-70 metabolismus MeSH
- receptory antigenů T-buněk imunologie metabolismus MeSH
- T-lymfocyty imunologie metabolismus MeSH
- tyrosin metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH