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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 19; pp. 8724 - 8729
• Main Authors: Govern, Christopher C, Paczosa, Michelle K, Chakraborty, Arup K, Huseby, Eric S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.05.2010; National Acad Sciences
• Subjects: Animals; Antigens; Biological Sciences; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Cellular receptors; Half-Life; Histocompatibility Antigens - immunology; Immunity; Kinetics; Ligands; Lymphocyte Activation - immunology; Membranes; Mice; Mice, Inbred C57BL; Modeling; Models, Immunological; Peptides; Peptides - immunology; Proofreading; Protein Binding - immunology; Receptors; Receptors, Antigen, T-Cell - immunology; Solubility; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1000966107

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.