Genetic and mutational analysis of the T-cell antigen receptor

Abstract

The studies reviewed here exploit the fact that the TCR is a multisubunit complex whose perturbation initiates an assortment of biochemical pathways and diverse biological responses. The creation and analysis of T cells bearing aberrant TCRs has led to a number of important conclusions and provided a framework for some educated speculation about T-cell biology. The assembly of the TCR is a highly regulated process in which the majority of the synthesized material is rapidly degraded. Partial complexes, which potentially might interfere with ligand binding by, or the function of, complete receptor molecules, are not tolerated; this "architectural editing" is performed in a compartment(s) associated with the ER or, in some cases, lysosomes. The individual chains of the TCR can be separated into subgroups that are, perhaps, functionally autonomous. The disulfide-linked variable chains bind ligand. The zeta eta heterodimer appears to be largely responsible for coupling receptor occupancy to PI hydrolysis, the zeta 2 heterodimer may couple to tyrosine kinase activation and/or other signaling pathways. The zeta 2-containing receptors are fully capable of transducing signals leading to IL-2 production and growth inhibition, while the presence of the zeta eta heterodimer is associated with the autolytic response of T-cell hybridomas to activation. Finally, an intact and functional TCR must be present for optimal expression of some, although not all, manifestations of activation that are initiated via independent cell-surface molecules such as Thy-1, Ly-6, and CD2. Future experiments in which TCR chains that incorporate site-directed mutations are transfected into T and non-T cells are certain to enhance our appreciation of how the structure of this receptor determines its many biological attributes.