The dynamics of T cell receptor signaling: Complex orchestration and the key roles of tempo and cooperation

T cells constantly sample their environment using receptors (TCR) that poss ess both a germline-encoded low affinity for major histocompatibility compl ex (MHC) molecules and a highly diverse set of CDR3 regions contributing to a range of affinities for specific peptides bound to these MHC molecules. The decision of a T cell "to sense and to respond" with proliferation and e ffector activity rather than "to sense, live on, but not respond" is depend ent on TCR interaction with a low number of specific foreign peptide:MHC mo lecule complexes recognized simultaneously with abundant self peptide-conta ining complexes. Interaction with self-complexes alone, on the other hand, generates a signal for survival without a full activation response. Current models for how this distinction is achieved are largely based on translati ng differences in receptor affinity for foreign versus self ligands into in tracellular signals that differ in quality, intensity, and/or duration. A v ariety of rate-dependent mechanisms involving assembly of molecular oligome rs and enzymatic modification of proteins underlie this differential signal ing. Recent advances have been made in measuring TCR:ligand interactions, i n understanding the biochemical origin of distinct proximal and distal sign aling events resulting from TCR binding to various ligands, and in apprecia ting the role of feedback pathways. This new information can be, synthesize d into a model of how self and foreign ligand recognition each evoke the pr oper responses from T cells, how these two classes of signaling events inte ract, and how pathologic responses may arise as a result of the underlying properties of the system. The principles of signal spreading and stochastic resonance incorporated into this model reveal. a striking similarity in me chanisms of decision-making among T cells neurons, and bacteria.