@article{54af40f000214d318404a1ebf3299bb0,
title = "Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination",
abstract = "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.",
author = "Lo, {Wan Lin} and Shah, {Neel H.} and Rubin, {Sara A.} and Weiguo Zhang and Veronika Horkova and Fallahee, {Ian R.} and Ondrej Stepanek and Zon, {Leonard I.} and John Kuriyan and Arthur Weiss",
note = "Funding Information: We thank A. Roque (University of California, San Francisco) for animal husbandry, S. Muratcioglu (University of California, Berkeley) for providing the GFP-labeled PLC-γ1 tandem N-SH2 protein, the NIH Tetramer Core Facility for providing the OVA and APL peptide-loaded H-2Kb monomers or OVA-loaded H-2Ab tetramers, the UCSF Parnassus Flow Cytometry Core for maintaining the BD FACSAria II, R. Mathieu (Boston Children{\textquoteright}s Hospital) and the BCH Department of Hematology/ Oncology Flow Cytometry Research Facility for technical assistance, B. Au-Yeung (Emory University), P. Allen and D. Donermeyer (Washington University in St. Louis), and G. Morris and L.-F. Lu (University of California, San Diego) for critical feedback on the manuscript. The work was supported by the Jane Coffin Childs Fund 61–1560 (to W.-L.L.), the Damon Runyon Cancer Research Foundation DRG 2198-14 and DFS 31-18 (to N.H.S.), the Czech Science Foundation 19-03435Y (to O.S.), the Howard Hughes Medical Institute (to A.W. and J.K.) and NIH, NIAID P01 AI091580-06 (to A.W. and J.K.), 1R37AI114575 (to A.W.), and DRC Center Grant P30 DK063720 (UCSF Parnassus Flow Cytometry Core). All data to understand and access the conclusions of this study are available in the main text, the supplementary materials, and the indicated repositories. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = nov,
day = "1",
doi = "10.1038/s41590-019-0502-2",
language = "English",
volume = "20",
pages = "1481--1493",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "11",
}