he inability to amplify signals in the absence of F-actin. It is not known how the TCR microclusters continue to move to the center of the synapse when the F-actin conveyor belt stops 1–2 μm from the center. This could be a diffusive process or might involve some alternative transport system that remains to be described. For example, the zone of F-actin depletion is observed in cytotoxic T cell synapses and allows close approach of the centrosome to the plasma membrane for efficient directed secretion (Stinchcombe et al., 2006).
It is not clear why F-actin is so important for TCR signal transduction because anti-CD3 stimulation to Ca2+ mobilization and cytokine production doesn’t require intact F-actin (Valitutti et al., 1995a). Similarly, B cells require F-actin to recognize ligands on a surface, but not aggregating ligands in solution. Stimulation by surface presented ligands requires F-actin, Rap1 and CD19 (Depoil et al., 2008; Lin et al., 2008). The model for stimulation of activation of BCR by monovalent ligands in supported planar bilayers is based on diffusion trapping of receptors and ligands in microdomains with multiple BCR and ligands. This mode of clustering is likely driven by F-actin dependent membrane fluctuations and adhesion, perhaps accounting for the role of F-actin in enhancing B cell recognition of solid phase ligands (Carrasco et al., 2004; Tolar et al., 2008). For T cells, the F-actin requirement seems to involve both forming microclusters and then formation of signaling complexes at the TCR clusters. This is based on the observation that many TCR microclusters are stable after F-actin depolymerization, but signaling is still terminated even though the receptor clusters persist. All antigen receptors engage in signaling that activates actin polymerization via the Rac and Cdc42 small G-proteins leading to activation of the WAVE2 complexes and WASp (Barda-Saad et al., 2005; Nolz et al., 2006). In the absence of WAVE2 the lamellipodium at the periphery of T cell contacts with anti-CD3 coated s