olamine (Brown and London, 2000). I would speculate that TCR maybe confined to approximately 10% of the plasma membrane composed of disordered, fluid phase and acidic lipids, which are corralled by the mobile actin elements. In the basal state the TCR cannot be individually transported into less acidic liquid ordered domains (Fig 2). Clustering of the receptors by serial ligand binding can stabilize the interaction with the F-actin meshwork and create a sufficient force to overcome resistance to entry into less acidic domains, in which the ITAMs are exposed in the presence of Src family kinases and with depletion of CD45 together lead to triggering of the signaling cascade (Fig 2). It is likely the the “lipid rafts” also anchored to disctinct cortical actin networks and this actin may anchor these domains against movement by the dendritic actin network inivolved in the retrograde flow (Chichili and Rodgers, 2007). This model invokes shearing action of the lamellipodial actin to generate force to overcome energetic barriers, similar to recent models for the role of lateral mechanical forces in integrin activation (Zhu et al., 2008).
The specific adapters that link TCR to F-actin are not well described. The complex may include NCK, SLP-76, ADAP, SKAP55, EVL, Vav, Rac, Cdc42 and WASP certainly may play a role once signaling is initiated (Barda-Saad et al., 2005; Bubeck Wardenburg et al., 1998; Krause et al., 2000). It has also been suggested that ZAP-70 may play a role through binding of ezrin (Ilani et al., 2007). It appears that TCR signaling in microclusters ceases when the microcluster reaches the actin depleted cSMAC. Since activated TCR appear equipped to generate their own dynamic actin focus, the suppression of this mode of actin dymanics in the cSMAC is likely to be active, rather than a passive dissipation of lamellar actin. Less is known about the basal interactions of TCR with actin that might be available to stabilize a cluster early in the triggering process. This is likely a complex situation. An exam