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 t1/2 of the interaction and the other based on the equilibrium affinity (KD). Here, we have identified and studied an extensive set of T-cell receptor (TCR)-peptide-MHC (pMHC) interactions for CD4+ cells that have differential KDs and kinetics of binding. Our data indicate that ligands with a short t1/2 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 t1/2 (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 t1/2-dependent when they have slow kon. Thus, TCR-pMHC kon allow high-affinity short t1/2 ligands to follow a kinetic proofreading model.

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