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

Nature volume 464, pages 932–936 (2010)Cite this article

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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 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 analysed three-dimensionally (3D) with a varying degree of correlation with the T-cell responsiveness2,3,4. Here we use two mechanical assays5,6 to show high 2D affinities between a TCR and its antigenic pMHC 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 slowest2,3,4. 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 intrinsic TCR–pMHC binding to generate broad affinities and rapid kinetics that determine T-cell responsiveness.

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Figure 1: Micropipette and BFP.
Figure 2: 2D kinetics measurements.
Figure 3: Comparison of 2D and 3D kinetics.
Figure 4: Correlation between 2D kinetics and T-cell proliferation.

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Change history

  • 12 April 2010

    In the online–only Methods, Pa was changed to Passoc in three places on 12 April 2010. Please see the erratum at the end of the PDF for details.

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Acknowledgements

We thank the NIH Tetramer Core Facility at Emory University for providing MHC monomers, J. Altman for providing the H-2Kb mutant construct, G. Bao for providing the divalent streptavidin, as well as M. Davis and H.-T. He for commenting on the manuscript. This work was supported by NIH grants AI38282 and AI060799 (to C.Z.) and NS062358, and National Multiple Sclerosis Society Grant RG4047-A-3 (to B.D.E.).

Author Contributions N.J. and C.Z. initiated the research with F5 T cells; J.H. and C.Z. designed the kinetic study; J.H. and B.L. performed the micropipette experiments; V.I.Z. performed the BFP experiments and Monte Carlo simulations; L.J.E. and B.D.E. provided the T cells and conducted the functional study; J.H., V.I.Z., B.L. and C.Z. analysed the data; B.D.E. and C.Z. wrote the paper with all authors contributing.

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Author notes

  1. Jun Huang & Ning Jiang

    Present address: Present addresses: Department of Microbiology and Immunology and The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA (J.H.); Department of Bioengineering, Stanford University, Stanford, California 94305, USA (N.J.).,

Authors and Affiliations

  1. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA,

    Jun Huang, Veronika I. Zarnitsyna, Baoyu Liu, Ning Jiang & Cheng Zhu

  2. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA,

    Lindsay J. Edwards & Brian D. Evavold

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Correspondence to Brian D. Evavold or Cheng Zhu.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 with legends and Supplementary Movie legends. (PDF 1058 kb)

Supplementary Movie 1

In this movie we see micropipette adhesion frequency assay (see Supplementary Information file for full legend). (MOV 3871 kb)

Supplementary Movie 2

In this movie we see BFP adhesion frequency assay (see Supplementary Information file for full legend). (MOV 4566 kb)

Supplementary Movie 3

In this movie we see BFP thermal fluctuation assay (see Supplementary Information file for full legend). (MOV 267 kb)

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Huang, J., Zarnitsyna, V., Liu, B. et al. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464, 932–936 (2010). https://doi.org/10.1038/nature08944

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