A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2.

Nolan, Sean; Vignali, Marissa; Klinger, Mark; Dines, Jennifer N.; Kaplan, Ian M.; Svejnoha, Emily; Craft, Tracy; Boland, Katie; Pesesky, Mitch; Gittelman, Rachel; Snyder, Thomas M.; Gooley, Christopher J; Semprini, Simona; Cerchione, Claudio; Mazza, Massimiliano; Delmonte, Ottavia M.; Dobbs, Kerry; Carreño‐Tarragona, Gonzalo; Barrio, Santiago; Sambri, Vittorio; Martinelli, Giovanni; Goldman, Jason D.; Heath, James R.; Notarangelo, Luigi D.; Carlson, Jonathan M.; Martínez‐López, Joaquín; Robins, Harlan

doi:10.21203/rs.3.rs-51964/v1

Cited by 134 publications

(228 citation statements)

References 9 publications

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“…We investigated the degree to which the MIRA enrichment strategy employed by Nolan et al (2020) identified TCRs with identical or similar amino acid sequences. In general, across multiple MIRA TCR β-chain antigen-enriched repertoires, the proportion of amino acid TCR sequences observed more than once was generally lower than in the tetramer-enriched repertoires and varied considerably across the sets; some MIRA sets resembled tetramer-sorted sub-repertoires (Figure 1B; see MIRA133), while others were more similar to unenriched repertoires (Figure 1B; see MIRA90).…”

Section: Frameworkmentioning

confidence: 99%

“…(A) Framework: sets of CD8+ TCRs activated by SARS-CoV-2 peptides were previously discovered in 61 individuals diagnosed with COVID-19 using a Multiplex Identification of Antigen-Specific T Cell Receptors Assay (MIRA) by Nolan et al (2020). For each TCR clone activated by a given peptide, we used tcrdist3 to evaluate the repertoire fraction spanned at different TCRdist radii within (i) its antigen enriched repertoire (black) and (ii) a control V- and J-gene matched, inverse probability weighted background repertoire (purple).…”

Section: Frameworkmentioning

confidence: 99%

“…Researchers used an assay based on antigen stimulation and flow cytometric sorting of activated CD8+ T cells to sequence SARS-CoV-2 peptide-associated TCR β-chains; the assay is called “multiplex identification of T-cell receptor antigen specificity” or MIRA (Klinger et al, 2015). Data from these experiments were released publicly in July 2020 by Adaptive Biotechnologies and Microsoft as part of ‘immuneRACE’ and their efforts to stimulate science on COVID-19 (Nolan et al, 2020; Snyder et al, 2020). The MIRA antigen enrichment assays identified 269 sets of TCR β-chains associated with CD8+ T cells activated by exposure to SARS-CoV-2 peptides, with TCR sets ranging in size from 1 - 16,607 TCRs (Table S1).…”

Section: Introductionmentioning

confidence: 99%

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TCR meta-clonotypes for biomarker discovery with tcrdist3: identification of public, HLA-restricted SARS-CoV-2 associated TCR features

Mayer-Blackwell

Schattgen

Cohen-Lavi

et al. 2020

Preprint

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As the mechanistic basis of adaptive cellular antigen recognition, 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 antigen-enriched repertoires to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires. We apply the framework to TCR data from COVID-19 patients, generating 1,915 public TCR meta-clonotypes from the 18 SARS-CoV-2 antigen-enriched repertoires with the strongest evidence of HLA-restriction. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 44% (845/1915) were significantly enriched among COVID-19 patients that expressed the putative restricting HLA allele, 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 workflows for distance-based TCR repertoire analysis.

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Section: Frameworkmentioning

confidence: 99%

Section: Frameworkmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TCR meta-clonotypes for biomarker discovery with tcrdist3: identification of public, HLA-restricted SARS-CoV-2 associated TCR features

Mayer-Blackwell

Schattgen

Cohen-Lavi

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…B-cell linear and discontinuous epitope prediction tools have been used by researchers to identify possible SARS-CoV-2 epitopes (23)(24)(25). Several more recent studies experimentally determined SARS-CoV-2 immune epitopes (11,26,27). Interestingly, several groups have reported signi cant T-cell reactivity against SARS-CoV-2 epitopes in individuals without virus exposure (22,26,28,29).…”

Section: Introductionmentioning

confidence: 99%

Identification of evolutionarily stable sites across the SARS-CoV-2 proteome

Wang

Konecki

Marciano

et al. 2020

Preprint

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Since the first recognized case of COVID-19, more than 30 million people have been infected worldwide. Despite global efforts in drug and vaccine development to fight the disease, there is currently no vaccine or drug cure for COVID-19, though some drugs reduce severity and hasten recovery. Here we interrogate the evolutionary history of the entire SARS-CoV-2 proteome to identify functional sites that can inform the search for treatments. Combining this information with the mutations observed in the current COVID-19 outbreak, we systematically and comprehensively define evolutionarily stable sites that are useful drug targets. Several experimentally-validated effective drugs interact with these proposed target sites. In addition, the same evolutionary information can prioritize cross reactive antigens that are useful in directing multi-epitope vaccine strategies to illicit broadly neutralizing immune responses to the betacoronavirus family. Although the results are focused on SARS-CoV-2, these approaches are based upon evolutionary principles and are agnostic to organism or infective agent.

show abstract

“…B-cell linear and discontinuous epitope prediction tools have been used by researchers to identify possible SARS-CoV-2 epitopes (23)(24)(25). Several more recent studies experimentally determined SARS-CoV-2 immune epitopes (11,26,27). Interestingly, several groups have reported significant T-cell reactivity against SARS-CoV-2 epitopes in individuals without virus exposure (22,26,28,29).…”

Section: Introductionmentioning

confidence: 99%