I. Introduction

The function of the T cell receptor (TCR) is unique in the pantheon of immune recognition. Unlike antibodies, which recognize foreign antigen in its native form, the TCR must bind antigenic peptide fragments as they are presented by major histocompatibility complex (MHC) molecules on the surface of neighboring cells. The TCR thus has an inherent dual specificity in its ability to associate with self MHC molecules while discriminating between numerous antigenic and benign peptide fragments.

Furthermore, selection of the T cell repertoire in the thymus is based upon recognition of self peptide fragments, as the healthy thymus is largely devoid of foreign antigen. Mature T cells are then selected for their potential to bind foreign peptide complexed to self MHC, as predicted from the TCR's affinity for self peptide complexed to self MHC. Only those thymocytes which recognize self MHC molecules are positively selected, while those which avidly bind and react to these molecules are negatively selected to prevent autoimmune reactions. Developing thymocytes expressing a TCR with low to moderate affinity for self peptide complexed to self MHC are exclusively allowed to mature and enter the periphery, where they are challenged with foreign antigen in the context of self MHC.

In addition to the dual specificity for self MHC and foreign peptide, the thymic selection process indicates another duality inherent in the TCR complex. Namely, the TCR must deliver a variety of activation signals to the interior of the T cell. In concert with co-receptors like CD4, CD8, and CD3, the TCR is able to deliver a weak or partial signal for thymic selection, as well as a robust signal for activation and clonal expansion when presented with foreign antigen. The mechanisms for this discrimination by the TCR remain unclear, although two major hypotheses have been proposed.

Like many other receptors, the TCR may aggregate upon binding its ligand, with dimers or other multimers initiating autophosphorylation and intracellular signaling cascades. In this case, the affinity of the TCR for its ligand would dictate the degree of aggregation, and the quantity of aggregate multimers would determine the strength of the activation signal. Alternatively, the TCR monomer may act as the control point, with ligand binding resulting in a conformational change in the receptor, thus leading to intracellular activation. In this scenario, the quality of ligand binding would directly determine the strength of the activation signal, as only high affinity binding could affect the conformational change necessary to induce activation.

The recent structural evaluation of an ab T cell receptor sheds new light on the nature of TCR antigen recognition and intracellular activation. While definitive answers have yet to be provided, it is clear that the structure of the TCR has specifically evolved to meet its unique function. The structure at right is the crystallographic structure of a murine ab T cell antigen receptor designated clone 2C. The 2C TCR was cloned from murine cytotoxic T cells restricted to the syngeneic class I MHC molecule H-2K^b. In the following tutorial, the animations (click buttons) can be performed in any order within each topic heading, and the molecule may be manipulated freely before and after the animations.