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

Abstract

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 playa role in antigen recognition, function as affinity-enhancing allosteric effectors that interact with the constant portion of the T-cell receptor.

Antigen-specific, MHC nonrestricted T helper cell-induced B cell activation.

“…The other is a low-affinity (or normally inaccessible) MHC-binding site which is induced to increase its affinity for (or is exposed to bind) polymorphic class II determinants only after the binding site for foreign antigen has been engaged. This model is consistent with recent reports (10-11) that the T cell receptor may bind nominal antigen in the absence of MHC molecules, and is compatible with allosteric models (12,13) of T cell receptor function that involve cooperativity between the nominal antigen and the MHC binding sites. Our experiments do not distinguish between a single a-,0 chain complex that contains both binding sites and the possibility that a second T cell surface receptor binds self MHC .…”

Identification of I-A β-chain residues critical for T cell recognition of peptide antigens

“…Antigens. hFPB (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) was obtained from Bachem (Torrance, CA). HEL (whole protein, Sigma Grade I) was purchased from Sigma (St. Louis, MO).…”

“…This "dual-recognition" process has multiple implications for the development and functions of the immune system and has thus been the focus of a large volume of research. A number of models for MHC-restricted antigen recognition have been advanced over the last several years (2)(3)(4)(5)(6)(7), with the consensus revolving around the idea of a three-membered antigen recognition complex composed of the TCR, antigen, and restricting MHC molecires. The exact relationships among and interactions between these three elements, however, have yet to be detailed, even for a single specific case.…”