The immunological synapse forms as a result of the tight apposition of a T cell with an antigen-presenting cell (APC) and it is the site where the T-cell receptor (TCR) is triggered by its antigen ligand, the peptide-MHC complex present in the APC membrane. The immunological synapse was initially characterized in the T-cell membrane as three concentric rings of membrane receptors and their underlying cytoskeletal and signalling proteins. The inner circle, or central supramolecular activation cluster (cSMAC), concentrates most of the TCR and CD28, and it is surrounded by the peripheral SMAC that is formed by integrins. Finally, the most external ring or distal SMAC (dSMAC) is where proteins with large ectodomains are located, such as CD43 and CD45, far from the cSMAC. This arrangement was initially thought to be responsible for maintaining sustained TCR signalling, however, this typical concentric bull's-eye pattern is not found in the immunological synapses formed with the APCs of dendritic cells. Interestingly, TCR signalling has been detected in microclusters formed in the dSMAC area and it extinguishes as the TCRs reach the cSMAC. Hence, it appears that TCR signalling and full T-cell activation do not require the formation of the cSMAC and that this structure may rather play a role in TCR down-regulation, as well as participating in the polarized secretion of lytic granules. Here, we shall review the historical evolution of the role of the cSMAC in T-cell activation, finally discussing our most recent data indicating that the cSMAC serves to internalize exhausted TCRs by phagocytosis.
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