re 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 microclusters (Tseng et al., 2008). Blocking TCR signaling with anti-MHC-peptide antibodies rapidly eliminated the bright CD28-CD80 foci, consistent with a continual role for TCR signaling in maintaining this component of the cSMAC. These studies demonstrate that the cSMAC consists of two compartments: one a stable structure enriched in non-signaling TCR destined for shedding or degradation (a) and one highly dynamic structure rich in F-actin, CD28 and PKC-θ (b) (table 1). These compartments are difficult to resolve in cSMACs formedin cell-cell interfaces. The mechanisms by which CD28 and TCR are segregated into these two cSMAC compartments is not known.
The mechanism of TCR triggering has been an enduring problem. The prevailing model has been based on TCR dimerization or clustering as a triggering modality (Germain, 1997; Weiss and Littman, 1994). This is largely based on models from receptor tyrosine kinases and observations that antibody crosslinking triggers signaling. However, the is an adapter that recruits no