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 killing (Baetz et al., 1995). Stabilization of the pSMAC of CD4+ cytotoxic T lymphocyte (CTL) with a PKC-θ inhibitor quantified increased killing, the first evidence of for an advantage of an intact pSMAC (Beal et al., 2008). Structures similar to pSMACs also form between T cells in homotypic aggregates and are important for intensification of cytokine signals during T cell expansion (Sabatos et al., 2008). The symmetric immunological synapse may serve equally important functions in tolerance induction, priming and differentiation as discussed below.
Between chemokine dependent extravasation and MHC-peptide dependent immunological synapse formation T cells rapidly migrate in DC networks of T cell zones (Bajenoff et al., 2006). Rapid migration by T cells can be fully reconstituted with solid phase CCL21, a CCR7 ligand, in vitro (Woolf et al., 2007). This involved polarization and formation of a leading edge that takes the form of a flattened lamellipodium on CCL21 and ICAM-1 coated surfaces (Huang and Dustin, unp