Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lo, W-L; Shah, NH; Rubin, SA; Zhang, W; Horkova, V; Fallahee, IR; Stepanek, O; Zon, LI; Kuriyan, J; Weiss, A

Published Date

  • November 2019

Published In

Volume / Issue

  • 20 / 11

Start / End Page

  • 1481 - 1493

PubMed ID

  • 31611699

Pubmed Central ID

  • 31611699

Electronic International Standard Serial Number (EISSN)

  • 1529-2916

Digital Object Identifier (DOI)

  • 10.1038/s41590-019-0502-2


  • eng

Conference Location

  • United States