TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs.
TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs.
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DOI：
10.7554/elife.68605
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发表时间：
2021-11-30
期刊：
影响因子：
7.7
通讯作者：
Fiore-Gartland A
中科院分区：
文献类型：
--
作者：
Mayer-Blackwell K;Schattgen S;Cohen-Lavi L;Crawford JC;Souquette A;Gaevert JA;Hertz T;Thomas PG;Bradley P;Fiore-Gartland A
T细胞受体（TCR）编码有临床价值的信息，反映先前的抗原暴露和潜在的未来反应。然而，尽管在深度库测序方面取得了进展，但巨大的TCR多样性使TCR克隆型作为临床生物标志物的使用复杂化。我们提出了一个新的框架，利用实验推断的抗原相关的TCR形成元克隆型-生物化学相似的TCR组-可用于稳健地量化功能相似的TCR在个体之间的批量库。我们将该框架应用于来自COVID-19患者的TCR数据，从SARS-CoV-2抗原相关TCR中生成了1831个公共TCR元克隆型，这些TCR有强有力的证据表明仅限于具有特定人类白细胞抗原（HLA）基因型的患者。应用于独立的队列，与精确的氨基酸匹配相比，靶向这些特异性表位的元克隆型在批量库中更频繁地被检测到，并且59.7%（1093/1831）在表达假定限制性HLA等位基因的COVID-19患者中更丰富（假发现率[FDR]<0.01），证明了元克隆型作为用于生物标志物开发的抗原特异性特征的潜在效用。为了实现进一步的应用，我们开发了一个开源软件包tcrdist 3，它实现了这个框架，并促进了基于距离的TCR库分析的灵活工作流程。
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.