Hypothesis: The MHC-restricted T-cell receptor as a structure with two multistate allosteric combining sites

Abstract

This paper presents a dual-recognition model of the T-cell receptor that has been constructed to account for the phenomenon of MHC restriction as well as the paradoxical ability of T-cells to be both multispecific and precisely specific at the same time. In our model the combining sites for antigen and MHC are not independent as in classical dual-recognition models, but interact with each other by an allosteric mechanism. We envision a flexible receptor with combining sites for antigen and MHC that are capable of existing in a multitude of distinct complementarity states. MHC and antigen molecules act as allosteric effectors such that one ligand perturbs the conformation and therefore the specificity of the site for the other ligand. An essential feature of the model is that different MHC determinants induce different conformations at the anti-antigen site. In this way the receptor acquires multiple specificities. Within a particular complementarity state, precise recognition results from the requirement that antigen and MHC exhibit positive cooperativity in their binding to the T-cell receptor. Positive cooperativity is also the basis for MHC restriction. Reaction mechanisms are presented which describe the requirement that antigen and MHC both induce conformational changes in order to generate high-affinity binding to either ligand. As a precedent for the multistate allosteric receptor model, we discuss the properties of allosteric enzymes, especially ribonucleotide reductase, whose properties are analogous to those we have postulated for the T-cell receptor. Also discussed is the possibility that molecules such as Ly2, L3T4 and the Mis antigen, which have been found to play a role in antigen recognition, function as affinity-enhancing allosteric effectors that interact with the constant portion of the T-cell receptor.