ases 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 