Fast on-rates allow short dwell time ligands to activate T cells

Abstract

Two contrasting theories have emerged that attempt to describe T-cell ligand potency, one based on the t[subscript 1/2] of the interaction and the other based on the equilibrium affinity (K[subscript D]). Here, we have identified and studied an extensive set of T-cell receptor (TCR)-peptide-MHC (pMHC) interactions for CD4⁺ cells that have differential K[subscript D]s and kinetics of binding. Our data indicate that ligands with a short t[subscript 1/2] can be highly stimulatory if they have fast on-rates. Simple models suggest these fast kinetic ligands are stimulatory because the pMHCs bind and rebind the same TCR several times. Rebinding occurs when the TCR-pMHC on-rate outcompetes TCR-pMHC diffusion within the cell membrane, creating an aggregate t[subscript 1/2] (ta) that can be significantly longer than a single TCR-pMHC encounter. Accounting for ta, ligand potency is KD-based when ligands have fast on-rates (kon) and t[subscript 1/2]-dependent when they have slow kon. Thus, TCR-pMHC kon allow high-affinity short t[subscript 1/2] ligands to follow a kinetic proofreading model.