cell stably appended onto the often-larger target cells like an apse on a building-which is the origin of the term synapse. In one study, a distinct annular adhesive domain and central secretory domains were resolved by electron microscopy (Schmidt et al., 1988), which foreshadows the later work by Kupfer.
The molecular organization of these interfaces was not revealed until advances in imaging in the 1990’s led to the definition of discrete localization of TCR and LFA-1 and a more specific definition of immunological synapse was proposed (Dustin et al., 1998). Springer proposed in 1990 that LFA-1 and TCR would be segregated in adhesive interfaces because they are different sizes and it would be impossible for TCR to reach the MHC in a adhesive interface mediated by LFA-1 and it would be similarly difficult for LFA-1 to squeeze into an interface defined by the smaller CD2-CD58 adhesion system, which would in turn be ideal for the TCR (Springer, 1990). Springer further proposed that exclusion of large phosphatases like CD45 might be important for tyrosine phosphorylation down-stream of the tyrosine kinase cascade. This concept has been refined and tested and seems likely to be an important part of the signaling niche for the TCR (Choudhuri and van der Merwe, 2007; Varma et al., 2006). Springer didn’t speculate on the scale over which this segregation process would take place. The initial answers to this question were surprising. Kupfer examined fixed T cell-B cell conjugates and revealed a large central TCR cluster that was also rich in PKC-θ, defined as the central supramolecular activation cluster (cSMAC) (Monks et al., 1998)(Table 1). A ring of LFA-1-ICAM-1 interactions and talin surrounds this central cluster, defined as the peripheral supramolecular activation cluster (pSMAC). Each of these areas contained thousands of molecules in what was apparently a large non-covalent functional network-a supramolecular assembly. Kupfer later defined the distal supramolecular activation cluster as the outermost structure, enriched in CD45, although this will be discussed further below. The distal pole complex was described by Burkhardt and may be important for sequestering specific negative regulators like SHP-1 (Cullinan et al., 2002). TCR microclusters will be discussed at length. Table I outlines the compartments associated with stable, antigen specific T cell-B cell conjugates.
Parallel studies with supported planar bilayers presenting adhesion molecules revealed similar phenomena in which a single adhesion system would establish a cooperative supamolecular cluster and mixed systems would segregate into spatially discrete SMACs. We examined the organization of the CD2-CD58 and LFA-1-ICAM-1 interactions in contacts in Jurkat T cells on planar bilayers containing ICAM-1 and CD58 (Dustin et al., 1998). We proposed that the “specialized junction, cell polarization, and positional stability” of the symmetric contacts were similar to a neural synapse and proposed that stable T-APC interfaces should be defined as “immunological synapses”. A planar bilayer based system using MHC-peptide complexes and LFA-1 fully recapitulated Kupfer’s findings and provided insight into the dynamics of these structures, which were not formed en bloc, but evolved from very distinct early intermediates by an F-actin dependent transport process (Grakoui et al., 1999)(Fig 1). The immunological synapse has an axis of radial symmetry with its center at the cSMAC (Fig 1). At the same time, we can view the synapse as having a direction of polarity along the length of this axis with a proximal and distal pole relative to the APC containing distinct molecules (Fig 1). The function of the immunological synapse pattern is most transparent for cytotoxic T cells where the F-actin free cSMAC serves as a secretory domain and the pSMAC serves as a retaining wall (Beal et al., 2008; Stinchcombe et al., 2006). The importance of directed secretion is supported by studies with human patients with deficiencies in granule transport to the synapse that lead to defects in kil