urfaces is lost (Nolz et al., 2006). This does not alter that ability of these cells to initiate early TCR signaling in response to solid phase anti-CD3, but more work is needed to determine if this alters sensitivity to MHC-peptide ligands as expected.
The recent focus on microclusters raises questions about cSMAC-associated signals. Is the cSMAC just for signal termination or is it a site of TCR or other relevant signaling? Is the cSMAC even one compartment? Kupfer defined the cSMAC based on accumulation of TCR and PKC-θ. Dynamic studies using fluorescence recovery after photobleaching (FRAP) revealed that TCR-MHC-peptide interactions are particularly stable in the cSMAC (Grakoui et al., 1999) and that the TCR microclusters that converge to form the cSMAC appear to fuse together into one stable structure on planar bilayers (Varma et al., 2006). This structure is partly shed by the T cell if it breaks the synapse and migrates or wanes over 10’s of minutes in stable synapses. Is this highly stabilized structure in which TCR seem to be shed or degraded all there is to the cSMAC? Analysis of CD28-CD80 interactions in the synapse suggests that there is a second, more dynamic component to the cSMAC that is typically not well resolved, but represents a very distinct sub-cellular compartment (Tseng et al., 2008; Yokosuka et al., 2008). CD28-CD80 interactions colocalize with TCR-MHC-peptide interactions in microclusters. When these mixed microclusters reach the cSMAC, mostof the TCR are incorporated into a stable central cluster, but all of the CD28 remains in an intermediate compartments which is very dynamic and appears to be critical for sustained PKC-θ signaling (Yokosuka et al., 2008). This annular structure sits at the inside edge of the F-actin rich lamella and thus the small amounts of TCR in this compartment may continue to signal to maintain the dynamic CD28-CD80 interactions. Similar segregation of TCR and CD28 is observed in T cell-DC interfaces, although it was not possible to observe the precursor microclu