Elementary Steps in T Cell Receptor Triggering

The mechanism by which antigen binding to the T cell antigen receptor (TCR) generates intracellular signaling, a process termed TCR triggering, is incompletely understood. A large body of experimental evidence has implicated multiple biophysical/biochemical effects and multiple molecules in the process of TCR triggering, which likely reflect the uniquely demanding role of the TCR in recognizing diverse antigenic ligands. In this perspective, I propose that breaking down the process of TCR triggering into tractable elementary steps may be a useful approach in building mechanistic TCR triggering models. Once these elementary steps are understood, they can be recombined to build a unified model of TCR triggering.

[1]  T. Finkel,et al.  T cell receptor triggering by force. , 2010, Trends in immunology.

[2]  Nigel J. Burroughs,et al.  Matched Sizes of Activating and Inhibitory Receptor/Ligand Pairs Are Required for Optimal Signal Integration by Human Natural Killer Cells , 2010, PloS one.

[3]  T. Harder,et al.  Plasma membrane rafts engaged in T cell signalling: new developments in an old concept , 2009, Cell Communication and Signaling.

[4]  P. Love,et al.  ITAM-mediated signaling by the T-cell antigen receptor. , 2010, Cold Spring Harbor perspectives in biology.

[5]  T. Höfer,et al.  Versatile regulation of multisite protein phosphorylation by the order of phosphate processing and protein–protein interactions , 2007, The FEBS journal.

[6]  Mark M. Davis,et al.  The Safety on the TCR Trigger , 2008, Cell.

[7]  Omer Dushek,et al.  Constitutively Active Lck Kinase in T Cells Drives Antigen Receptor Signal Transduction , 2010, Immunity.

[8]  Mi-Hua Tao,et al.  Cutting Edge: Mechanical Forces Acting on T Cells Immobilized via the TCR Complex Can Trigger TCR Signaling , 2010, The Journal of Immunology.

[9]  Omer Dushek,et al.  Mechanisms for T cell receptor triggering , 2011, Nature Reviews Immunology.

[10]  Author,et al.  Qualitative and Quantitative Differences , 2007 .

[11]  Linda J Pike,et al.  Heterogeneity in EGF-binding affinities arises from negative cooperativity in an aggregating system , 2008, Proceedings of the National Academy of Sciences.

[12]  K Lund,et al.  Implications of epidermal growth factor (EGF) induced egf receptor aggregation. , 1992, Biophysical journal.

[13]  S. Jameson,et al.  Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands. , 1999, Immunity.

[14]  Omer Dushek,et al.  Ultrasensitivity in multisite phosphorylation of membrane-anchored proteins. , 2011, Biophysical journal.

[15]  Jun Ma,et al.  Activation of the innate immune receptor Dectin-1 upon formation of a “phagocytic synapse” , 2011, Nature.

[16]  J. Gunawardena,et al.  Unlimited multistability in multisite phosphorylation systems , 2009, Nature.

[17]  Simon J Davis,et al.  The kinetic-segregation model: TCR triggering and beyond , 2006, Nature Immunology.

[18]  T. Höfer,et al.  Multisite protein phosphorylation – from molecular mechanisms to kinetic models , 2009, The FEBS journal.

[19]  Chang Shin Park,et al.  Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts* , 2003, Journal of Biological Chemistry.

[20]  Qing Nie,et al.  Nonessential sites improve phosphorylation switch. , 2010, Biophysical journal.

[21]  E. Reinherz,et al.  Mechanisms Contributing to T Cell Receptor Signaling and Assembly Revealed by the Solution Structure of an Ectodomain Fragment of the CD3ϵγ Heterodimer , 2001, Cell.

[22]  Oreste Acuto,et al.  Tailoring T-cell receptor signals by proximal negative feedback mechanisms , 2008, Nature Reviews Immunology.

[23]  Christopher Garcia Faculty Opinions recommendation of Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. , 2002 .

[24]  Mark M. Davis,et al.  Ligand-specific oligomerization of T-cell receptor molecules , 1997, Nature.

[25]  E. Reinherz,et al.  Mechanisms contributing to T cell receptor signaling and assembly revealed by the solution structure of an ectodomain fragment of the CD3 epsilon gamma heterodimer. , 2001, Cell.

[26]  Terrence P. Kenakin,et al.  A Pharmacology Primer: Theory, Application and Methods , 2004 .

[27]  Zhengyu Ma,et al.  Surface-Anchored Monomeric Agonist pMHCs Alone Trigger TCR with High Sensitivity , 2008, PLoS biology.

[28]  Christer S. Ejsing,et al.  Accumulation of raft lipids in T‐cell plasma membrane domains engaged in TCR signalling , 2009, The EMBO journal.

[29]  D. Colquhoun,et al.  Binding, gating, affinity and efficacy: The interpretation of structure‐activity relationships for agonists and of the effects of mutating receptors , 1998, British journal of pharmacology.

[30]  Balbino Alarcón,et al.  Recruitment of Nck by CD3ϵ Reveals a Ligand-Induced Conformational Change Essential for T Cell Receptor Signaling and Synapse Formation , 2002, Cell.