| First Author | Lo WL | Year | 2019 |
| Journal | Nat Immunol | Volume | 20 |
| Issue | 11 | Pages | 1481-1493 |
| PubMed ID | 31611699 | Mgi Jnum | J:292899 |
| Mgi Id | MGI:6436151 | Doi | 10.1038/s41590-019-0502-2 |
| Citation | Lo WL, et al. (2019) Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination. Nat Immunol 20(11):1481-1493 |
| abstractText | 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-gamma1 (PLC-gamma1), 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-gamma1 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. |
