An induced rebinding model of antigen discrimination

Abstract

T cells have to detect rare high-affinity 'foreign' peptide MHC (pMHC) ligands among abundant low-affinity 'self'-peptide MHC ligands. It remains unclear how this remarkable discrimination is achieved. Kinetic proofreading mechanisms can provide the required specificity but only at the expense of much reduced sensitivity. A number of recent observations suggest that pMHC engagement of T cell receptors (TCRs) induces changes such as clustering and/or conformational alterations that enhance subsequent rebinding. We show that inclusion of induced rebinding to the same pMHC in kinetic proofreading models enhances the sensitivity of TCR recognition while retaining specificity. Moreover, induced rebinding is able to reproduce the striking, and hitherto unexplained, 2D membrane-binding properties recently reported for the TCR.

Figure 1

Induced rebinding of T cell receptors improves antigen discrimination. (A) Schematic illustrating that T cells need to exhibit a response only to ligands with a dissociation time (τ = 1/k_off) above a threshold (vertical line) even when only a single ligand is displayed (horizontal line) while not responding to ligands below the threshold even when displayed in large numbers. (B) The fraction of pMHCs that remain bound to the TCR over time for six pMHCs for the dissociation times indicated in units of s (for 3D) or ms (for 2D). Increasing the threshold binding time (vertical line) improves specificity because these lines diverge, but at the cost of sensitivity, because in all cases the fraction of pMHC that remains bound decreases exponentially. (C) Direct calculation of the response curves (analogous to panel A) for the standard kinetic proofreading model and kinetic proofreading with constitutive or induced rebinding for the threshold time indicated. (D) Schematic of kinetic proofreading with induced rebinding. Note that both 3D and reduced 2D dissociation times are shown (top panels). Coloured circles in panels A and C correspond to the six pMHCs indicated in panel B. Details of the model formulation, calculation, and parameter values can be found in Box 1 and in the supplementary material online.

Figure 2

Induced rebinding modulates the fitted 2D TCR–pMHC binding parameters in adhesion frequency assays. In adhesion frequency assays, a T cell and a pMHC-bearing cell are brought into contact for a specific period of time before adhesion (i.e., pMHC binding) is measured. We used the induced rebinding model to simulate the adhesion frequency assay by (A) calculating the concentration of bound pMHC over time for six pMHC ligands with (B,C) the 3D solution binding parameters indicated. (D) The adhesion frequency (or probability of adhesion) is calculated for these six pMHC ligands based on the concentration of bound pMHC. (E,F) A fitting procedure is implemented to determine the fitted 2D membrane-binding parameters. Induced rebinding introduces large variance in the fitted 2D on-rates (despite no difference in the 3D on-rates) and produces negative correlation between the 3D and fitted 2D off-rates, as experimentally observed. See the supplementary material online for fitting details.