 vivo will be needed to drill deeper into T cell signaling (Oddos et al., 2008).
The relationship between TCR microclusters and F-actin suggests that the TCR clusters are formed actively rather than by diffusion trapping by ligand alone. The formation of TCR microclusters is F-actin dependent whether the ligand is a physiological MHC-peptide complex or a CD3 antibody (Bunnell et al., 2001; Campi et al., 2005; Douglass and Vale, 2005; Varma et al., 2006). This also extends to signaling because depolymerization of actin in an established synapse results in rapid cessation of signaling, but does not disrupt larger TCR microclusters or the cSMAC (Varma et al., 2006). The synapse contains a zone of F-actin depletion at the center, corresponding to the cSMAC regardless of whether this structure is filled with TCR (Kaizuka et al., 2007). When TCR clusters reach the actin free zone in the center the signaling process appears to be terminated. The mechanism of signal termination is not known, but may be as simple as the 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