The discriminatory power of the T cell receptor

T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (pMHC) antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have h...

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Autores principales:	Johannes Pettmann, Anna Huhn, Enas Abu Shah, Mikhail A Kutuzov, Daniel B Wilson, Michael L Dustin, Simon J Davis, P Anton van der Merwe, Omer Dushek
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	T cells T cell receptor co-signalling receptors antigen discrimination kinetic proofreading mathematical model Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/bcd2f1d193024b08b393a17283f277a4
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spelling	oai:doaj.org-article:bcd2f1d193024b08b393a17283f277a42021-11-17T13:18:16ZThe discriminatory power of the T cell receptor10.7554/eLife.670922050-084Xe67092https://doaj.org/article/bcd2f1d193024b08b393a17283f277a42021-05-01T00:00:00Zhttps://elifesciences.org/articles/67092https://doaj.org/toc/2050-084XT cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (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.Johannes PettmannAnna HuhnEnas Abu ShahMikhail A KutuzovDaniel B WilsonMichael L DustinSimon J DavisP Anton van der MerweOmer DushekeLife Sciences Publications LtdarticleT cellsT cell receptorco-signalling receptorsantigen discriminationkinetic proofreadingmathematical modelMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	T cells T cell receptor co-signalling receptors antigen discrimination kinetic proofreading mathematical model Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	T cells T cell receptor co-signalling receptors antigen discrimination kinetic proofreading mathematical model Medicine R Science Q Biology (General) QH301-705.5 Johannes Pettmann Anna Huhn Enas Abu Shah Mikhail A Kutuzov Daniel B Wilson Michael L Dustin Simon J Davis P Anton van der Merwe Omer Dushek The discriminatory power of the T cell receptor
description	T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (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.
format	article
author	Johannes Pettmann Anna Huhn Enas Abu Shah Mikhail A Kutuzov Daniel B Wilson Michael L Dustin Simon J Davis P Anton van der Merwe Omer Dushek
author_facet	Johannes Pettmann Anna Huhn Enas Abu Shah Mikhail A Kutuzov Daniel B Wilson Michael L Dustin Simon J Davis P Anton van der Merwe Omer Dushek
author_sort	Johannes Pettmann
title	The discriminatory power of the T cell receptor
title_short	The discriminatory power of the T cell receptor
title_full	The discriminatory power of the T cell receptor
title_fullStr	The discriminatory power of the T cell receptor
title_full_unstemmed	The discriminatory power of the T cell receptor
title_sort	discriminatory power of the t cell receptor
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/bcd2f1d193024b08b393a17283f277a4
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The discriminatory power of the T cell receptor

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