Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 19, Pages 8724-8729Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1000966107
Keywords
affnity; kinetic proofreading; MHC; rebinding; T cell receptor
Categories
Funding
- Beckman Young Investigator and Searle Scholars Award
- National Institutes of Health [1P01AI07/1195/01]
- National Institutes of Health Biotechnology Training Program grant
- University of Massachusetts Diabetes Endocrinology Research Center [DK32520]
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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(D)s and kinetics of binding. Our data indicate that ligands with a short t(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(1/2) (t(a)) that can be significantly longer than a single TCR-pMHC encounter. Accounting for ta, ligand potency is K(D)-based when ligands have fast on-rates (k(on)) 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.
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