The discriminatory power of the T cell receptor
- University of Oxford, United Kingdom
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
P Anton van der Merwe
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).
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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The discriminatory power of the T cell receptor
eLife 10:e67092.
https://doi.org/10.7554/eLife.67092
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