ling (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a leading edge that takes the form of a flattened lamellipodium on CCL21 and ICAM-1 coated surfaces (Huang and Dustin, unpublished data). LFA-1 is not required for mobility in T cell zones (Woolf et al., 2007), but LFA-1 increases sensitivity to MHC-peptide complexes up to 100-fold (Bachmann et al., 1997) and ICAM-1 is required for antigen specific arrest in vivo (Scholer et al., 2008). The lamellipodium is a sensory structure and has been shown to be the most sensitive part of a T cell by ~40-fold in elegant studies with laser traps and anti-CD3 coated beads (Negulescu et al., 1996; Wei et al., 1999). Valitutti has also described the probing behavior of lymphocytes undergoing sustained signaling on APCs (Valitutti et al., 1995a). Another important experiment is the demonstration that TCR signaling is continually being renewed by new TCR-MHC-peptide interactions such that blocking the access to new MHC-peptide ligands with MHC antibodies immediately block signaling (Valitutti et al., 1995a).
Lamellipodia are coordinated by small G-proteins including Rac-1, which activates the WAVE2 complexes leading to dynamic actin in the perip