T cell recognition of antigen: Immunological synapse formation, activation and differentiatio

T cell recognition of antigen is the critical step in the generation of an immune response. T cells recognize antigen in the form of short polypeptides presented by MHC molecules on APCs. Since the MHC molecules do not discriminate between the ligands they present, the TCR must be keenly responsive, be able to discern between relevant and irrelevant antigenic complexes, and decipher self from nonself. The exquisite sensitivity of the interaction, specific recognition of the ligand, and discriminatory nature of the TCR orchestrate a regulated polarization of extracellular molecules followed by an elaborate signal transduction cascade.;Real time imaging and quantitative digital fluorescence microscopy of MHC-peptide complexes in a T cell junction demonstrated three stages in TCR engagement: capture, central clustering and cluster stabilization. Our studies showed that formation of a specialized junction, the immunological synapse, links kinetic discrimination of early TCR engagement to distinct spatial structures for sustained TCR signaling. These sustained signals through the TCR can generate activated T cells and differentially induce cytokines.;The failure of some ligands to fully activate T cells is due to a lack of sustained signaling. Altered peptide ligand (APL) stimulation failed to induce cyclin E: cdk2 activity, which in turn led to lack of phosphorylation of pRb and arrest at the G1/S transition. The integrity of the MHC-peptide ligand also has dramatic effects on Th cell development.;A study of the effects of antigen dose and APLs revealed that each peptide can induce Th2 cytokines at low concentrations and Th1 cytokines at high concentrations and that each has a unique range of concentrations at which these distinct effects occur. Moreover, we observed that at the single cell level, the ability of an individual T cell to become an IL-4 or IFNgamma producer is stochastic. These results suggested an existence of cross talk between T cells and APCs at the population level. The ability of the MHC-peptide to engage and select for the outgrowth and activation of a particular subset of T cells has fundamental implications for T cell biology.