Organization of the resting TCR in nanoscale oligomers

Abstract

Despite the low affinity of the T-cell antigen receptor (TCR) for its peptide/major histocompatibility complex (pMHC) ligand, T cells are very sensitive to their antigens. This paradox can be resolved if we consider that the TCR may be organized into pre-existing oligomers or nanoclusters. Such structures could improve antigen recognition by increasing the functional affinity (avidity) of the TCR-pMHC interaction and by allowing cooperativity between individual TCRs. Up to approximately 20 TCRs become tightly apposed in these nanoclusters, often in a linear manner, and such structures could reflect a relatively generalized phenomenon: the non-random concentration of membrane receptors in specific areas of the plasma membrane known as protein islands. The association of TCRs into nanoclusters can explain the enhanced kinetics of the pMHC-TCR interaction in two dimensional versus three dimensional systems, but also their existence calls for a revision of the TCR triggering models based on pMHC-induced TCR clustering. Interestingly, the B-cell receptor and the FcεRI have also been shown to form nanoclusters, suggesting that the formation of pre-existing receptor oligomers could be widely used in the immune system.

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

“…Ligand binding is thought to induce clustering of many cell surface receptors, including EGFR, T cell receptors, Ephrin receptors, and Toll-like receptors (33,34,61,62). Receptor clustering is dependent on many aspects, such as ligand affinity, ligand dissociation, the size of ligands, and the concentration of coactivators (63)(64)(65)(66).…”

Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms

“…Some aspects of TCR–pMHC molecular interactions that are of current research interest are the frequency of encounters between T cells and the agonist pMHC, how cell–cell interactions determine the activation of lymphocytes (2), how early interactions change the state of the T cell receptor (3), what are the mechanisms of modulation of receptor–ligand interactions at cell–cell interfaces (4), and how protein organization in the cell membrane (for instance, protein islands or lipid rafts) affects the recognition process (5). Some recent experiments have explored the role of dimensionality on T cell activation and have highlighted the significance of the events taking place at the receptor level [see Refs.…”

“…It has recently been suggested that, contrary to what happens in TCR micro-clusters and the immunological synapse, clustering is not only induced by the ligand but by an avidity maturation mechanism (or pre-clustering) (17), allowing the aggregation of chains of TCRs as long as 20 units (around 200 nm long), and referred to as nano-clusters (3, 18). Specifically, multimeric TCR–CD3 complexes are activated at low agonistic pMHC concentrations and monomeric TCRs remain unaffected at low ligand concentration.…”

“…The TCR nano-clusters could enhance T cell sensitivity by the mechanisms proposed in the models of T cell activation (7), as their existence would reduce the time needed for two (or more) receptors to aggregate (by diffusion). This pre-cluster formation could be explained by three different mechanisms (3): Multimeric complexes (or clusters) enhance the TCR avidity toward the ligand, which is expressed in clusters on the surface of APCs (19–21). At low ligand concentration, only multimeric TCR clusters are bound to ligand, as TCR monomers require higher ligand concentration.…”

Structure of the Chicken CD3ϵδ/γ Heterodimer and Its Assembly with the αβT Cell Receptor

“…In humans and other mammals, the TCR signaling complex comprises eight type-I membrane-spanning polypeptides that include the TCR ␣␤ heterodimer, the CD3⑀␥ and CD3⑀␦ heterodimers, and the CD3 homodimer (1), although higher order molecular assemblies are considered to exist (2,3). The ␣␤TCR functions to recognize peptide-, lipid-, and vitamin B precursor-based antigens that are presented by major histocompatibility complex (MHC) or MHC-like molecules (4 -7).…”