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

Two contrasting theories have emerged that attempt to describe T-cell ligand potency, one based on the t_1/2 of the interaction and the other based on the equilibrium affinity (K_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 _Ds and kinetics of binding. Our data indicate that ligands with a short t_1/2 can be highly stimulatory if they have fast onrates. 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_1/2 (t_a) that can be significantly longer than a single TCR-pMHC encounter. Accounting for t_a, ligand potency is K_D-based when ligands have fast on-rates (kon) and t _1/2-dependent when they have slow k_on. Thus, TCR-pMHC k_on allow high-affinity short t_1/2 ligands to follow a kinetic proofreading model.