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Sci. Signal., 4 March 2008
Vol. 1, Issue 9, p. ec79
[DOI: 10.1126/stke.19ec79]

EDITORS' CHOICE

Immunology Pulling on the TCR

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

The exact mechanism by which peptide-loaded major histocompatibility complex (pMHC) activates the T cell receptor (TCR) has been controversial. Various models have been proposed to account for the requirement of presentation by antigen-presenting cells (APCs) for effective TCR activation and the lack of activation by soluble pMHC, the ability of very low concentrations of agonist pMHC in the presence of endogenous pMHC to activate TCR signaling, and the apparent necessity of costimulatory interactions for effective activation. Ma et al. anchored pMHCs to either a fluid lipid bilayer or plastic surfaces and found that in the absence of nonagonist pMHC a minimum of 1 to 10 monomeric agonist pMHC (MCC-loaded pMHC) per T cell was sufficient to stimulate TCR signaling in T cells interacting with the artificial substrates. Furthermore, the T cell response (calcium signal) was not enhanced by the addition of nonagonist pMHC with the agonist pMHC or under conditions where the nonagonist pMHC and agonist pMHC were close enough to function as a dimer (by coupling to the same streptavidin molecule before covalent attachment to the artificial surface). To confirm that endogenous nonagonist pMHC did not enhance T cell activation in a more physiological situation, the authors loaded murine B cell lymphoma cells with various endogenous peptides and the MCC peptide and found that the production of interleukin-2 by the T cells was the same whether a previously reported costimulatory endogenous pMHC was present or not. The authors used another lipid bilayer system to which T cells would not bind unless the adhesion molecule ICAM was incorporated and found that adhesion was necessary for TCR triggering by MCC-loaded pMHC. When the T cells were treated with cytochalasin to depolymerize actin, the T cells failed to respond to MCC-loaded lymphoma cells or MCC-loaded pMHC bilayers or plastic surfaces, suggesting that the actin cytoskeleton is necessary for TCR triggering. The authors discuss how their results can be reconciled with the reports, suggesting that endogenous pMHC enhance T cell response to low-abundance agonist pMHC and propose a receptor deformation model for TCR activation. In their model, the agonist pMHC-TCR interaction leads to receptor deformation and activation when the cytoskeleton provides a pulling force on the complex. Endogenous pMHC-TCR interactions would be insufficiently strong to provide the necessary activation signal, and the complex would dissociate when "pulled on" by the cytoskeleton.

Z. Ma, K. A. Sharp, P. A. Janmey, T. H. Finkel, Surface-anchored monomeric agonist pMHCs alone trigger TCR with high sensitivity. PLoS Biol. 6, e43 (2008). [PubMed]

Citation: N. R. Gough, Pulling on the TCR. Sci. Signal. 1, ec79 (2008).



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