TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs

T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework...

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Autores principales:	Koshlan Mayer-Blackwell, Stefan Schattgen, Liel Cohen-Lavi, Jeremy C Crawford, Aisha Souquette, Jessica A Gaevert, Tomer Hertz, Paul G Thomas, Philip G Bradley, Andrew Fiore-Gartland
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	T cell receptor immune repertoire SARS-CoV-2 software biomarkers Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d1ecb3c26e0145ee974f654e715a1b6d
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spelling	oai:doaj.org-article:d1ecb3c26e0145ee974f654e715a1b6d2021-11-30T12:30:38ZTCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs10.7554/eLife.686052050-084Xe68605https://doaj.org/article/d1ecb3c26e0145ee974f654e715a1b6d2021-11-01T00:00:00Zhttps://elifesciences.org/articles/68605https://doaj.org/toc/2050-084XT-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.Koshlan Mayer-BlackwellStefan SchattgenLiel Cohen-LaviJeremy C CrawfordAisha SouquetteJessica A GaevertTomer HertzPaul G ThomasPhilip G BradleyAndrew Fiore-GartlandeLife Sciences Publications LtdarticleT cell receptorimmune repertoireSARS-CoV-2softwarebiomarkersMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	T cell receptor immune repertoire SARS-CoV-2 software biomarkers Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	T cell receptor immune repertoire SARS-CoV-2 software biomarkers Medicine R Science Q Biology (General) QH301-705.5 Koshlan Mayer-Blackwell Stefan Schattgen Liel Cohen-Lavi Jeremy C Crawford Aisha Souquette Jessica A Gaevert Tomer Hertz Paul G Thomas Philip G Bradley Andrew Fiore-Gartland TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs
description	T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.
format	article
author	Koshlan Mayer-Blackwell Stefan Schattgen Liel Cohen-Lavi Jeremy C Crawford Aisha Souquette Jessica A Gaevert Tomer Hertz Paul G Thomas Philip G Bradley Andrew Fiore-Gartland
author_facet	Koshlan Mayer-Blackwell Stefan Schattgen Liel Cohen-Lavi Jeremy C Crawford Aisha Souquette Jessica A Gaevert Tomer Hertz Paul G Thomas Philip G Bradley Andrew Fiore-Gartland
author_sort	Koshlan Mayer-Blackwell
title	TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs
title_short	TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs
title_full	TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs
title_fullStr	TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs
title_full_unstemmed	TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs
title_sort	tcr meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, hla-restricted clusters of sars-cov-2 tcrs
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/d1ecb3c26e0145ee974f654e715a1b6d
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TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs

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