T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity

Abstract

The interaction between the T-cell receptor (TCR) and its peptide-major histocompatibility complex (pepMHC) ligand plays a critical role in determining the activity and specificity of the T cell. The binding properties associated with these interactions have now been studied in many systems, providing a framework for a mechanistic understanding of the initial events that govern T-cell function. There have been various other reviews that have described the structural and biochemical features of TCR : pepMHC interactions. Here we provide an overview of four areas that directly impact our understanding of T-cell function, as viewed from the perspective of the TCR : pepMHC interaction: (1) relationships between T-cell activity and TCR : pepMHC binding parameters, (2) TCR affinity, avidity and clustering, (3) influence of coreceptors on pepMHC binding by TCRs and T-cell activity, and (4) impact of TCR binding affinity on antigenic peptide specificity.

Figure 1

Relationships among T-cell activity, T-cell receptor (TCR) equilibrium binding constants, and TCR dissociation kinetics. (a) Equilibrium binding constants K_D (affinity) and half-life (t_1/2) measurements for wild-type TCRs were plotted using published values shown in Table 1. Theoretical receptor (X) represents the binding parameters of a TCR that, if available, would provide additional insight into the mechanisms of T-cell activation as described in the text. (b) Equilibrium binding constants K_D (affinity) and half-life (t_1/2) measurements for TCRs engineered for high affinity, from published values shown in Table 2, were added to the data in (a). The type of T-cell activity (agonist, weak agonist, antagonist) mediated by each TCR is indicated by the symbols.

Figure 2

Simulated effect of T-cell receptor : peptide–major histocompatibility complex (TCR:pepMHC) association kinetics, dissociation kinetics, or TCR surface levels on pepMHC tetramer binding. Using a simplified multivalent binding model, simulated values and curves were generated to predict (a–c) number of pepMHC tetramers bound per T cell or (d–f) dissociation rates of bound tetramers from a T cell. The varied TCR parameters included the k_on (a,d), the k_off (b,e), and the R_tot [total number of TCRs per T cell (c,f)]. In each panel, the fixed parameters correspond to the 2C TCR binding to SIY/K^b (k_on = 20 000/m/second, k_off∼0·3/second, R_tot∼20 000 per cell) and the simulated result for 2C TCR is shown in red. In panels (a–c) the equilibrium tetramer staining was simulated using 200 nm pepMHC tetramer, and the grey hatched boxes encompass the region below 2000 molecules per cell, a ‘threshold’ below which there may be no binding detectable by flow cytometry (i.e. detected as ‘no staining’ above the contol). Panels (d–f) show simulated tetramer dissociation rates predicted by varying the indicated parameters. The potential contribution of CD8 to binding is not assessed.

Figure 3

Relationships among T-cell receptor (TCR) equilibrium binding constants, peptide specificity, and T-cell activity thresholds. For a given TCR, a variety of peptide ligands will have different stimulatory effects, depending on their binding affinity. The concept is highlighted using the 2C TCR system as a model. (a) Wild-type 2C is activated by a group of structurally similar peptides (of which SIY is the strong agonist) bound to K^b within a narrow affinity range, but only in the presence of the CD8 coreceptor. Those peptide–major histocompatibility complex (pepMHC) complexes that bind more weakly, such as dEV8/K^b, elicit antagonist signals. Complexes with even lower affinity are not stimulatory; they may give weak survival signals or be completely inactive (null). (b) By contrast, the high-affinity TCR 2Cm33 can be activated by agonist pepMHCs such as SIY/K^b without the CD8 coreceptor, and can be fully activated by the peptide dEV8 in the presence of CD8. This increase in affinity allows 2Cm33 to be stimulated by peptides with greater degrees of dissimilarity from wild-type, resulting in an apparent reduced ‘fine specificity’ by 2Cm33. (c) We refer to the ability of the TCR to distinguish between structurally unrelated peptides as ‘antigen specificity’ and the ability of the TCR to distinguish between structurally similar peptides (such as altered peptide ligands, in this case, of SIY) as ‘fine specificity’.