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

Wan Lin Lo, Neel H. Shah, Sara A. Rubin, Weiguo Zhang, Veronika Horkova, Ian R. Fallahee, Ondrej Stepanek, Leonard I. Zon, John Kuriyan, Arthur Weiss*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review


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.

Original languageEnglish
Pages (from-to)1481-1493
Number of pages13
JournalNature Immunology
Issue number11
Publication statusPublished - 1 Nov 2019
Externally publishedYes


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