s (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 are needed for sensitive recognition of rare MHC-peptide ligands. The links between TCR signaling and polarity networks include Cdc42 and PKC-ζ. Activation of Cdc42 has been extensively studied in T cells due to interest in immunodeficiencies such as Wiscott-Alrdrich Syndrome. PKC-ζ can be activated in the Par3-Par6 complex by activation of Cdc42, but it is not clear what it means that PKC-ζ is concentrated in the distal pole complex, the part of the T cell farthest from the synapse (Chang et al., 2007). The polarity networks control the positioning of actin, microtubules and intermediate filament and spindles. The dynamic F-actin networks and myosin II seem important at early stages of signaling complex assembly. The actin-myosin system is critical for multiple stages in TCR triggering and sustained signaling. It will be exciting in the future to determine in more detail how the context of TCR signaling allows this process to shape differentiation in parallel with powerful innate signals.
I thank Kaushik Chou