view will describe the cellular context of TCR signaling reactions, which include an important niche based on F-actin rich lamellipodia that can be elaborated in motile and arrested cells.
The TCR and adhesion molecules were identified by antibodies in the same burst of activity to discover the receptors involved in lymphocyte function by screening for inhibitors (Sanchez-Madrid et al., 1982; White et al., 1983). The last piece of the molecular puzzle, the structure of an MHC-peptide complex, was determined in 1987 (Bjorkman et al., 1987). This structure clarified the highly competitive nature of binding short peptides to the MHC molecule in a relatively stable manner (Babbitt et al., 1985). Thus, each TCR is locked into recognizing a small number of antigenic structures and each MHC molecule presents a single peptide. DCs use a limited numbers of any single MHC-peptide ligand to search through a vast repertoire of T cells. Thus, powerful mechanisms are needed to coordinate the search and response. Early work on the T cell signaling response to TCR-MHC-peptide interactions revealed rapid elevation of and protein kinase C activation and cytoplasmic Ca2+ down-stream of a tyrosine kinase cascade (Samelsonet al., 1986). Parallel studies on the adhesion molecule LFA-1 demonstrated that it was regulated by an F-actin and energy dependent mechanism that could be activated by phorbol esters (Marlin and Springer, 1987). LFA-1 was found to mediate adhesion by binding to a family of adhesion molecules including ICAM-1, whose expression reflects the innate immune activation of tissues (Dustin et al., 1986). Resting T cells are non-adhesive to ICAM-1 coated surfaces when freshly isolated from peripheral blood, but become more adhesive to ICAM-1 after triggering of TCR signaling (Dustin and Springer, 1989). The time course of adhesion activation closely followed the time course of TCR signaling: a process of “inside-out signaling” (Dustin and Springer, 1989). In the case of LFA-1, a candidate molecular mechanism for this activ