, signaling and cell biology of T cells.
The adaptive immune system is a sensory organ that monitors our inner spaces for evidence of infection or cancer, regulates steady state microbiota and avoids self injury (Krogsgaard and Davis, 2005). The primary filter for this sensor is the dendritic cell (DC), which samples tissue spaces and interfaces for novel macromolecular information (Steinman et al., 2003). DC respond to tissues injury and detect conserved microbial structures leading to changes in DC signals to T lymphocyte (T cells), to shape an appropriate response (Trombetta and Mellman, 2005; West et al., 2004). The largest part of the information is in the form of proteins broken down into peptides that form complexes with surface molecules of the major histocompatibility complex (MHC-peptide complexes) that allow DCs to share this information with T cells expressing the T cell antigen receptors (TCR). An individual has a few hundred T cells that can detect any foreign MHC-peptide complex with single molecule 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 re