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

eLife

Jeremy C Crawford¹  Jessica A Gaevert¹  Stefan Schattgen¹  Liel Cohen-Lavi²  Philip G Bradley³  Tomer Hertz⁴  Aisha Souquette⁵  Paul G Thomas⁵  Koshlan Mayer-Blackwell⁶  Andrew Fiore-Gartland⁶ 

[1] Department of Immunology, St Jude Children's Research Hospital, Memphis, United States;Department of Industrial Engineering and Management, Ben-Gurion University of the Negev, Be'er Sheva, Israel;Fred Hutchinson Cancer Research Center, Seattle, United States;Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Be'er Sheva, United States;St Jude Children's Research Hospital, Memphis, United States;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States;

关键词: T cell receptor;    immune repertoire;    SARS-CoV-2;    software;    biomarkers;    Human;   

DOI  :  10.7554/eLife.68605

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY