The kinetics of two dimensional TCR and pMHC interactions determine T cell responsiveness

• Type of Material: Article
• Authors: Jun Huang, Georgia Institute of Technology; Veronika I. Zarnitsyna, Georgia Institute of Technology; Baoyu Liu, Georgia Institute of Technology; Lindsay J. Edwards, Emory University; Ning Jiang, Georgia Institute of Technology; Brian Evavold, Emory University; Cheng Zhu, Georgia Institute of Technology
• Language: English
• Date: 2010-04-08
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Macmillan Publishers Limited. All Rights Reserved
• Final Published Version (URL): http://www.nature.com/nature/journal/v464/n7290/full/nature08944.html
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 464
• Issue: 7290
• Start Page: 932
• End Page: 936
• Grant/Funding Information: National Multiple Sclerosis Society Grant RG4047-A-3; NIH grants AI38282, AI060799, and AI056017
• Research Categories: Health Sciences, Immunology; Engineering, Biomedical; Biology, Microbiology

Abstract

The T cell receptor (TCR) interacts with peptide-major histocompatibility complexes (pMHC) to discriminate pathogens from self-antigens and trigger adaptive immune responses. Direct physical contact is required between the T cell and the antigen-presenting cell (APC) for cross-junctional binding where the TCR and pMHC are anchored on two-dimensional (2D) membranes of the apposing cells1. Despite their 2D nature, TCR-pMHC binding kinetics have only been analyzed three-dimensionally (3D) with a varying degree of correlation with the T cell responsiveness2-4. Here we use two mechanical assays5,6 to show high 2D affinities between a TCR and its antigenic pMHCs driven by rapid on-rates. Compared to their 3D counterparts, 2D affinities and on-rates of the TCR for a panel of pMHC ligands possess far broader dynamic ranges that match that of their corresponding T cell responses. The best 3D predictor of response is the off-rate, with agonist pMHC dissociating the slowest2-4. In contrast, 2D off-rates are up to 8,300-fold faster, with the agonist pMHC dissociating the fastest. Our 2D data suggest rapid antigen sampling by T cells and serial engagement of a few agonist pMHCs by TCRs in a large self pMHC background. Thus, the cellular environment amplifies the TCR-pMHC binding to generate broad affinities and rapid kinetics that determine T-cell responsiveness.