ecule sensitivity (Irvine et al., 2002; Sykulev et al., 1996). This sensitivity evolved by necessity because although the DC may express up to a million MHC molecules, it also samples thousands of proteins, most of which are self-proteins (Trombetta and Mellman, 2005). Thus, each T cell that contacts a DC needs to sort through this huge complexity of ligands and then focus on a few tens or hundreds of ligands that bind the TCR. This ultrasensitive process is still poorly understood, but clues are being discovered at an accelerating rate such that some critical answers are on the horizon. In the 1980’s it was shown that antigen recognition and actin dependent adhesion were integrated processes (Dustin and Springer, 1989); in the 1990’s it was discovered that the actin rich lamellipodium was the most sensitive part of this sensitive cells (Valitutti et al., 1995a); and in the present decade we and others have begun to examine single molecule dynamics of TCR signaling complexes (Douglass and Vale, 2005). This review 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 activation was binding of talin to the cytoplasmic domain of LFA-1 (Smith et al., 2005). Talinis recruited to sites of LFA-1 interaction with ligands on APCs and this is a more sensitive process with respect to antigen dose than cytokine production or proliferation (Kupfer and Singer, 1989). The parallel field studying lymphocyte trafficking revealed that LFA-1 can also be acutely activated by G-protein coupled receptors that are associated with lymphocyte homing (Lawrence and Springer, 1991). Thus, LFA-1 regulation is a cornerstone in both body-wide navigation of lymphocytes through vascular interaction and the coordination of antigen recognition and strong, transient adhesion leading to the immunological synapse in tissues.
Specific signaling pathways are required for inside out signaling from TCR to LFA-1. The adapter molecule ADAP and its partner SKAP-55 have been shown to contribute to about half of TCR triggered adhesion (Peterson et al., 2001). This process is integrated with F-actin at both the level of th