Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition
van der Merwe PA, Davis SJ, Shaw AS, Dustin ML. (2000), Semin Immunol. 12, 5-21
T cell antigen recognition is accompanied by cytoskeletal polarization towards the APC and large-scale redistribution of cell surface molecules into ‘supramolecular activation clusters’ (SMACs), forming an organized contact interface termed the ‘immunological synapse’ (IS). Molecules are arranged in the IS in a micrometer scale bull’s eye pattern with a central accumulation of TCR/peptide-MHC (the cSMAC) surrounded by a peripheral ring of adhesion molecules (the pSMAC). We propose that segregation of cell surface molecules on a much smaller scale initiates TCR triggering, which drives the formation of the IS by active transport processes. IS formation may function as a checkpoint for full T cell activation, integrating information on the presence and quality of TCR ligands and the nature and activation state of the APC.
Key figure: The kinetic-segregation model of TCR triggering and immunological synapse formation
The redistribution of cell surface molecules (depicted as in Figure 3) in T cell activation. The green and red boxes on the left are enlarged views of the boxes on the right. (i) Before cell-cell contact the TCR CD3 complex is subject to constitutive tyrosine phosphorylation and dephosphorylation. Dephosphorylation dominates, leading to a low steady-state level of tyrosine phosphorylation. (ii) Initial T cell contact with an APC leads the formation of multiple close-contact zones within the contact area as a result of small-scale segregation of molecules. This is a passive process driven by size and ligand binding. Within these close-contact zones tyrosine phosphorylation is favoured because tyrosine phosphatases (e.g. CD45) are excluded, and tyrosine kinases are concentrated. (iii) Engagement by TCR of specific-peptide-MHC occurs within these close-contact zones and results in the trapping of the TCR CD3 complex within a zone for a period, the length of which is determined primarily by the stability of the TCR peptide-MHC complex. While in the zone, TCR CD3 is tyrosinephosphorylated, initiating the multi-step signalling process required for triggering. (iv) A sufficiently stable TCR peptide-MHC interaction (complex II) allows these signalling steps to be completed, leading to triggering. Unstable complexes (I and III) lead to no or partial triggering because, on leaving the close-contact zone, TCR CD3, and any recruited signalling molecules, are re-exposed to high levels of tyrosine-phosphatase activity. (v) TCR triggering initiates active large-scale segregation of molecules, culminating in the formation of the mature IS. (vi) Steps (ii) to (v) are enhanced by ‘co-stimulatory signals’ such as chemokines or the expression of CD28 ligands on APCs. (vii) Sustained signalling through the IS results in full T cell activation.