The immunological synapse: a cause or consequence of T-cell receptor triggering?

Abstract

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.

Figure 1

T-cell receptor (TCR) internalization from the immunological synapse (IS). The cartoon depicts the formation of a classical IS between a T cell and either an antigen-presenting cell (APC) or a supported planar bilayer, which are not shown for simplicity. In resting T cells, the TCR is forming pre-existing nanometer-scale oligomers that are called TCR nanoclusters. A few seconds after recognition of the antigen peptide major histocompatibility complex (pMHC) on the APC membrane, the TCR starts forming larger oligomers that are visible in the light microscope and are called microclusters (MC). In these MC the TCR is associated with co-stimulatory receptors (CD28) to tyrosine kinases (Lck and ZAP70), serine kinases [protein kinase C (PKCθ)] and adaptor molecules (LAT, SLP76). Signals transmitted by TCR MC promote the polymerization of the actin cytoskeleton in the form of an expanding ring that spreads the T cell's membrane on the pMHC-loaded APC's membrane. This spreading of the T cell's membrane allows the interaction of more TCRs with new pMHC ligands. From this point of maximal expansion (a), the IS starts to contract resulting from a contraction of the peripheral actin ring (b). At this point, a centripetal movement of TCR MC is observed in which kinases and adaptors are being released from the TCR MC resulting in the accumulation on the centre of the IS of TCR MC not apparently associated with signalling proteins. New signalling MC are continuously formed at the periphery of the IS, which continuously migrate towards the centre of the IS. This process leads to the formation of the classical bull's-eye pattern of a mature IS (c) in which the TCR concentrates in an internal ring essentially devoid of signalling proteins called the central supramolecular activation cluster (cSMAC). The periphery of the cSMAC is still decorated with CD28 and PKCθ. The cSMAC is surrounded by a ring of integrins (peripheral SMAC; pSMAC), which is also surrounded by a more distal ring (the dSMAC) of membrane proteins like CD43 and CD45 with large ectodomains. The expanding and contracting actin rings are indicated by green circles. The cSMAC is devoid of polymerized actin. (d) The TCR can be endocytosed by a clathrin-dependent mechanism (green arrow) from the pSMAC and other areas external to the cSMAC and is also internalized from the cSMAC by a clathrin-independent phagocytic mechanism (red arrow) that is accompanied by the trogocytosis of APC membrane fragments containing pMHC. This figure has been inspired by Yokosuka et al.