Cutting edge: Evidence for a dynamically driven T cell signaling mechanism.

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TitleCutting edge: Evidence for a dynamically driven T cell signaling mechanism.
Publication TypeJournal Article
Year of Publication2012
AuthorsHawse, WF, Champion, MM, Joyce, MV, Hellman, LM, Hossain, M, Ryan, V, Pierce, BG, Weng, Z, Baker, BM
JournalJ Immunol
Volume188
Issue12
Pagination5819-23
Date Published2012 Jun 15
ISSN1550-6606
KeywordsAnimals, Computational Biology, HLA-A2 Antigen, Humans, Lymphocyte Activation, Peptide Fragments, Protein Structure, Quaternary, Receptors, Antigen, T-Cell, Signal Transduction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Surface Plasmon Resonance, T-Lymphocytes, Urokinase-Type Plasminogen Activator
Abstract

T cells use the αβ TCR to bind peptides presented by MHC proteins (pMHC) on APCs. Formation of a TCR-pMHC complex initiates T cell signaling via a poorly understood process, potentially involving changes in oligomeric state, altered interactions with CD3 subunits, and mechanical stress. These mechanisms could be facilitated by binding-induced changes in the TCR, but the nature and extent of any such alterations are unclear. Using hydrogen/deuterium exchange, we demonstrate that ligation globally rigidifies the TCR, which via entropic and packing effects will promote associations with neighboring proteins and enhance the stability of existing complexes. TCR regions implicated in lateral associations and signaling are particularly affected. Computational modeling demonstrated a high degree of dynamic coupling between the TCR constant and variable domains that is dampened upon ligation. These results raise the possibility that TCR triggering could involve a dynamically driven, allosteric mechanism.

DOI10.4049/jimmunol.1200952
Alternate JournalJ. Immunol.
PubMed ID22611242
PubMed Central IDPMC3375328
Grant ListGM067079 / GM / NIGMS NIH HHS / United States
GM084884 / GM / NIGMS NIH HHS / United States
R01 GM067079 / GM / NIGMS NIH HHS / United States
RR025761 / RR / NCRR NIH HHS / United States