Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/13297
Title: A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function
Authors: Lo, Wan-Lin
Kuhlmann, Miriam
Rizzuto, Gabrielle
Ekiz, H. Atakan
Kolawole, Elizabeth M.
Revelo, Monica P.
Andargachew, Rakieb
Keywords: T-Cell
LAT protein
Lymphocyte antigen receptor
Amino acid substitution
Phosphoproteins
Publisher: Nature Portfolio
Abstract: Mature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LAT(G135D)) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LAT(G135D) T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LAT(G135D) T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LAT(G135D) show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity. Lo and colleagues provide evidence for the TCR kinetic proofreading model by LAT Gly135Asp alteration to reveal functional consequences of altered kinetics in TCR activation in thymic selection and mature T-cell responses.
URI: https://doi.org/10.1038/s41590-023-01444-x
https://hdl.handle.net/11147/13297
ISSN: 1529-2908
1529-2916
Appears in Collections:Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection

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