Fast on-rates allow short dwell time ligands to activate T cells
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Fast on-rates.pdf
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Author(s)
Paczosa, M. K.
Huseby, E. S.
Govern, Christopher Calbone
Chakraborty, Arup K
Date Issued
April 2010
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Govern, C. C.; Paczosa, M. K.; Chakraborty, A. K. and Huseby, E. S. “Fast on-Rates Allow Short Dwell Time Ligands to Activate T Cells.” Proceedings of the National Academy of Sciences 107, no. 19 (April 2010): 8724–8729. © 2010 National Academy of Sciences
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1073/pnas.1000966107
