Evolving concepts of specificity in immune reactions

Abstract

Our goal is to provide a perspective on current understanding of the origins of specificity in immune reactions, a topic that has intrigued scientists for over a century. A fundamental property of adaptive immune responses is the ability to discriminate among an immense variety of substances by means of antibodies (Abs) and Ab-like receptors on T lymphocytes [T-cell receptors (TCRs)], each able to bind a particular chemical structure [the antigen (Ag)] and not, or only weakly, similar alternatives. Evidence has long existed, however, and has grown, especially recently, that while exhibiting remarkable specificity, many individual Abs and TCRs can also bind a variety of very different ligands. How can Ag recognition by these receptors exercise the great specificity for which they are renowned and yet react with a variety of different ligands (degeneracy)? We critically consider the mechanistic bases for this specificity/degeneracy enigma and also compare and contrast Ag recognition by Abs and TCRs.

Fig. 1.

General scheme for Ag recognition by Ab. (Upper) Various free Ab conformers bind different Ags (e.g., Ag₁, Ag₂), but only one complex (or a few) persists long enough for further conformational changes to occur (induced fit) and yields strong Ab-Ag binding. (Lower) Conformers can bind various Ags to different subsites in the conformers’ combining site, thereby locking the Ab into a single conformation that binds different Ags. *, **, and *** represent different Ab conformations.

Fig. 2.

Maturation of Ag-stimulated B cells. Ag (X)-stimulated naive B cells (I) proliferate and acquire mutations in Ab V domains (II), yielding progeny cells that express cell-surface Abs that differ in their affinity for the Ag (lower affinity, open symbols; higher affinity, closed symbols) and in their ability to bind just a few ligands (V domain, rectangles) or a variety of different ligands (V domains, irregular circles). Decreasing Ag levels selectively stimulate the higher affinity Ab-producing B cells (III), some of which become memory cells that can be restimulated later (IV) by an Ag that is the same as the original (X), a variant of it (X′), or structurally entirely different (Y) to produce higher affinity relatively specific (Upper) or multispecific (Lower) Abs.

Fig. 3.

Bar code model for specificity of TCR–pMHC interactions. The thickness of the lines in the cartoon is proportional to the strength of interactions between residues of the TCR CDR3 and those of the counterparty (epitope). After scanning the epitope and formation of an encounter complex (if conditions described in the text are met), modest changes in conformation of the TCR and, in some instances, of the epitope may ensue and lead to improved fit and strength of interactions.