1. Computational and Systems Biology
  2. Immunology and Inflammation
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The discriminatory power of the T cell receptor

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Cite this article as: eLife 2021;10:e67092 doi: 10.7554/eLife.67092

Abstract

T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities, and use it to measure the discriminatory power of the TCR, and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as KD ~1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4, S3, and S7 and Table S1 and S2.

Article and author information

Author details

  1. Johannes Pettmann

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1979-8943
  2. Anna Huhn

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  3. Enas Abu Shah

    Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5033-8171
  4. Mikhail A Kutuzov

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3386-4350
  5. Daniel B Wilson

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  6. Michael L Dustin

    Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
    Competing interests
    Michael L Dustin, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4983-6389
  7. Simon J Davis

    Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  8. P Anton van der Merwe

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9902-6590
  9. Omer Dushek

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    omer.dushek@path.ox.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5847-5226

Funding

Wellcome Trust (207537/Z/17/Z)

  • Johannes Pettmann
  • Anna Huhn
  • Enas Abu Shah
  • Mikhail A Kutuzov
  • Daniel B Wilson
  • Omer Dushek

Wellcome Trust (098274/Z/12/Z)

  • Simon J Davis

Wellcome Trust (100262Z/12/Z)

  • Michael L Dustin

Wellcome Trust (203737/Z/16/Z)

  • Johannes Pettmann

UCB-Oxford Post-doctoral Fellowship

  • Enas Abu Shah

National Science Foundation Division of Mathematical Sciences USA (NSF-DMS 1902854)

  • Daniel B Wilson

Edward Penley Abraham Trust Studentship

  • Anna Huhn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Ethical approval was provided by the Medical Sciences Inter-divisional Research Ethics Committee (IDREC) at the University of Oxford (R51997/RE001).

Reviewing Editor

  1. Frederik Graw, Heidelberg University, Germany

Publication history

  1. Received: January 30, 2021
  2. Accepted: May 15, 2021
  3. Accepted Manuscript published: May 25, 2021 (version 1)

Copyright

© 2021, Pettmann et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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