There is considerable controversy about the mechanism of T cell receptor (TCR) triggering, the process by which the TCR tranduces signals across the plasma membrane after binding to its ligand (an agonist peptide complexed with an MHC molecule). Three main types of mechanism have been proposed, which involve aggregation, conformational change and segregation. Here, we review recently published evidence for each type of mechanism and conclude that all three may be involved. This complexity may reflect the uniquely demanding nature of TCR-mediated antigen recognition, which requires the detection of a very weak 'signal' (very rare foreign peptide–MHC ligands) in the presence of considerable 'noise' (abundant self peptide–MHC molecules).
The activation of T cells is controlled by T cell receptor (TCR) engagement with peptide antigen presented on MHC molecules (peptide–MHC complexes). The process is uniquely challenging because of the very low abundance of foreign agonist peptide compared with the very high abundance of self peptide, leading to difficulties with discrimination of signal from noise.
TCR engagement leads to alterations in the cytoplasmic portions of the associated CD3 subunits, including phosphorylation of tyrosine residues, a process termed TCR triggering. The mechanisms that have been proposed for TCR triggering include aggregation, conformational change and segregation of the TCR.
The pseudodimer model postulates that self peptide–MHC complexes cooperate with foreign peptide–MHC complexes to induce TCR aggregation. Recent evidence that a large proportion of self peptide–MHC complexes can bind the TCR provides strong support for this model.
There has been renewed interest in conformational change models following the demonstration of conformational changes in the CD3 cytoplasmic domains and the finding that these changes could be induced by the pulling mechanical force that the TCR is subjected to upon peptide–MHC binding.
There is also evidence that segregation induced by ectodomain size differences or partitioning into membrane microdomains contributes to TCR triggering.
A model is proposed that incorporates and reconciles these aggregation, conformational change and segregation models, and postulates a role for TCR microclusters in signal/noise discrimination.
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We thank our many scientific colleagues and collaborators, including S. Cordoba, H. Zhang, S. Davis, T. Harder, M. Brown, N. Barclay and O. Acuto, for many valuable discussions and insights, and for communicating results before publication. We also thank the referees for their comments and suggestions.
The authors declare no competing financial interests.
- Immunoreceptor tyrosine-based activation motif
(ITAM). A sequence that is present in the cytoplasmic domains of the invariant chains of various cell-surface immune receptors, such as the T cell receptor–CD3 complex. Following phosphorylation of their tyrosine residue, ITAMs function as docking sites for Src homology 2 (SH2) domain-containing tyrosine kinases and adaptor molecules, thereby facilitating intracellular signalling cascades.
- Serial-triggering model
A model that was proposed to account for the observation that small numbers of agonist peptide–MHC complexes seemed to trigger large numbers of T cell receptors (TCRs), and that postulates that a given peptide–MHC complex can serially bind to and trigger multiple TCRs. As it is the number of productive TCR engagements that determines peptide–MHC efficacy, high-affinity peptide–MHC complexes with long half-lives may be less effective. According to this model there is an optimal affinity or half-life for a TCR–peptide–MHC complex.
- Kinetic proof-reading model
A model that was proposed to account for the ability of T cells to discriminate between peptide–MHC ligands that have small differences in their affinity or half-life. It postulates that T cell receptor (TCR) triggering requires multiple sequential steps that can only proceed while the TCR is engaged with a peptide–MHC complex and that are completely reversed as soon as the TCR dissociates from the complex.
- Lipid raft
An area of the plasma membrane that is rich in cholesterol, glycosphingolipids, glycosylphosphatidylinositol-anchored proteins and several signalling proteins — such as Src family kinases, LAT (linker for activation of T cells) and PAG (protein associated with glycolipid-enriched microdomains).These domains are also known as glycolipid-enriched microdomains (GEMs) and detergent-insoluble glycolipid-enriched membranes (DIGs).
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