 Wilson et al., 2001). The force needed to induce island mixing may be generated by periodic myosin II based contraction. This may account for the role of myosin IIA in the signal amplification from Lck, which is normally activated after myosin IIA knock-down, to ZAP-70 and LAT, which are only weakly activated in myosin IIA knock-down T cells (Ilani et al., 2009).
The TCR triggering process in microclusters and how this is sustained in a synapse has relevance to T cell decision-making. T cell differentiation is controlled in large part by cytokines and small molecules from APC. There are two independent reports that propose distinct mechanisms for the synapse to influence differentiation. One is the concentration of interferon-γ receptors in the synapse leading to increased T helper 1 (Th1) cell development (Maldonado et al., 2004). IL-4 counteracts this through Stat6 (Maldonado et al., 2004). The other is the control of polarity networks leading to asymmetric cell division to control memory-effector decisions (Chang et al., 2007; Ludford-Menting et al., 2005). A particular challenge is in understanding how the microcluster-based mechanism sustains signaling from small numbers of ligand to drive differentiation. If each microcluster can sustain signaling for 2 minutes as the microclusters translocates from the periphery to the cSMAC. How is signaling sustained with only 10 MHC-peptide complexes? An interesting observation is that although the actin depleted zone at the center of the synapse is always present, the size of the cSMAC is linearly dependent upon the MHC-peptide density such that no TCR cSMAC if formed at the lower limit of MHC-peptide density. Under these conditions our model would posit that MHC-peptide ligand are recycled expensively by long term serial triggering at the F-actin rich cSMAC-pSMAC boundary. This fits with notions of serial triggering initially propose by Valittuti and Lanzavechia (Valitutti et al., 1995b), but would induce very little if any TCR down-regulation because all receptors a