 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