Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination.
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.
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- ZAP-70 Protein-Tyrosine Kinase
- Tyrosine
- T-Lymphocytes
- Receptors, Antigen, T-Cell
- Phosphorylation
- Phospholipase C gamma
- Mice
- Membrane Proteins
- Male
- Lymphocyte Activation
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- ZAP-70 Protein-Tyrosine Kinase
- Tyrosine
- T-Lymphocytes
- Receptors, Antigen, T-Cell
- Phosphorylation
- Phospholipase C gamma
- Mice
- Membrane Proteins
- Male
- Lymphocyte Activation