Diagnosing Viral Infections Through T-Cell Receptor Sequencing of Activated CD8+ T Cells

J Infect Dis. 2024 Feb 14;229(2):507-516. doi: 10.1093/infdis/jiad430.


T-cell-based diagnostic tools identify pathogen exposure but lack differentiation between recent and historical exposures in acute infectious diseases. Here, T-cell receptor (TCR) RNA sequencing was performed on HLA-DR+/CD38+CD8+ T-cell subsets of hospitalized coronavirus disease 2019 (COVID-19) patients (n = 30) and healthy controls (n = 30; 10 of whom had previously been exposed to severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). CDR3α and CDR3β TCR regions were clustered separately before epitope specificity annotation using a database of SARS-CoV-2-associated CDR3α and CDR3β sequences corresponding to >1000 SARS-CoV-2 epitopes. The depth of the SARS-CoV-2-associated CDR3α/β sequences differentiated COVID-19 patients from the healthy controls with a receiver operating characteristic area under the curve of 0.84 ± 0.10. Hence, annotating TCR sequences of activated CD8+ T cells can be used to diagnose an acute viral infection and discriminate it from historical exposure. In essence, this work presents a new paradigm for applying the T-cell repertoire to accomplish TCR-based diagnostics.

Keywords: COVID-19; NGS-based diagnostics; T cells; TCR sequencing; immunoinformatics; immunology.

MeSH terms

  • CD8-Positive T-Lymphocytes*
  • COVID-19 Testing
  • COVID-19* / diagnosis
  • Epitopes
  • Epitopes, T-Lymphocyte
  • Humans
  • Receptors, Antigen, T-Cell / genetics
  • SARS-CoV-2
  • T-Lymphocyte Subsets


  • Receptors, Antigen, T-Cell
  • Epitopes
  • Epitopes, T-Lymphocyte