sters (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 non-receptor tyrosine kinases to 10 docking sites, the immunotyrosine based activation motifs (ITAMs), in response to ligand binding. With all these docking sites, it is not clear that dimerizing this receptor would increase its activity. Recent studies have provided indirect evidence that monovalent ligands can trigger TCR microclusters and signaling events without directly cross-linking the receptor to form dimers e.g.(Varma et al., 2006). It is interesting at this point to think about how the TCR would sense such a monovalent engagement event? Recent data from the BCR and TCR systems provide insights into accessibility changes in cytoplasmic domains of the receptor during triggering and provide raw material for a draft model that incorporates an early role for F-actin.
The BCR has two signal transduction subunits with one ITAM in each. BCR with a FRET donor at the C-terminus of transmembrane immunoglobulin (sIg) and a FRET acceptor on the C-terminus of Igα have a high FRET signal in the basal, non-signaling 