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