Kinetic discrimination in T-cell activation (T-cell receptor/antigen/major histocompatibility complex/reaction mechanism/antagonism)

We propose a quantitative model for T-cell activation in which the rate of dissociation of ligand from T-cell receptors determines the agonist and antagonist properties of the ligand. The ligands are molecular complexes between antigenic peptides and proteins of the major histocompatibility complex on the surfaces of antigenpresenting cells. Binding of ligand to receptor triggers a series of biochemical reactions in the T cell. If the ligand dissociates after these reactions are complete, the T cell receives a positive activation signal. However, dissociation of ligand after completion of the first reaction but prior to generation of the final products results in partial T-cell activation, which acts to suppress a positive response. Such a negative signal is brought about by T-cell ligands containing the variants of antigenic peptides referred to as T-cell receptor antagonists. Results of recent experiments with altered peptide ligands compare favorably with T-cell responses predicted by this model. In this paper we propose a model for both positive and negative triggering of T lymphocytes with special reference to the responsiveness of T-helper cells to T-cell receptor ligands on the surfaces of antigen-presenting cells. These ligands are molecular complexes of class II major histocompatibility complex (MHC) proteins and antigenic peptides. The background of this model is drawn from a number of sources. (i) Cell-cell recognition often involves weak but specific forces (1, 2). Measurements of the binding of isolated T-cell receptors and their ligands show that this binding is weak (3-5), with rapid dissociation of the ligand from T-cell receptor (t1/2 between 2 and 30 s at 25?C) (6, 7). (ii) It is known that relatively few (50-200) ligands are sufficient to activate T cells (8-10). Lanzavecchia and coworkers (11) have demonstrated that a small number of ligands are sufficient to down-regulate a large number of T-cell receptors. These results suggest that each ligand interacts sequentially with a large number of T-cell receptors, a process referred to as serial engagement. (iii) It has been discovered that when certain antigenic peptides are mutated, the mutated peptide may act as an antagonist, inhibiting T-cell responses to the antigenic peptide (ref. 12; reviewed in ref. 13). This inhibition is T-cell receptor specific and cannot be explained by competition for peptide binding to the MHC protein. (iv) Activation of T cells by agonist and antagonist ligands results in different intracellular biochemical events. Agonist activation is associated with complete T-cell receptor phosphorylation and activation of the tyrosine kinase ZAP-70, whereas antagonist activation is associated with partial T-cell receptor phosphorylation and failure to activate this kinase (14, 15). In our discussion, the term T-cell receptor refers to the receptor molecule itself (an af3 heterodimer), as well as The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. ?1734 solely to indicate this fact. associated proteins (the W; homodimer, CD3 protein, and related kinases). (v) Kinetic proofreading is a model in which the specificity of formation of a biochemical product is enhanced when the product is formed via a number of chemical steps, each of which tests the fidelity of a reaction intermediate (16). McKeithan (17) has proposed that because of kinetic proofreading, T-cell activation may depend strongly on the rate of dissociation of ligand from T-cell receptors. In this paper we expand on this idea by proposing that incomplete receptor activation is inhibitory and that antagonist ligands cause incomplete receptor activation. Kinetic Discrimination Model Consider the simplest possible kinetic model. A schematic depicting the essential components of this model is shown in Fig. 1. Assume a number of ligands on the surface of the antigen-presenting cell that is small (e.g., 100) compared to the number of T-cell receptors on the surface of a T cell (1-5 x 104). In a steady-state condition, ligand L binds to and dissociates from the T-cell receptor (R),