Introduction: T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection.
Methods: Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides. Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells.
Results: Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]).
Discussion: The approaches described in this work provide detailed insights into the adaptive immune response to SARS-CoV-2 infection, and they have potential applications in clinical diagnostics, vaccine development, and monitoring.
Keywords: COVID-19; SARS-CoV-2; T cell; TCR repertoire; cellular immunity; immune response.
Copyright © 2025 Snyder, Gittelman, Klinger, May, Osborne, Taniguchi, Jabran Zahid, Kaplan, Dines, Noakes, Pandya, Chen, Elasady, Svejnoha, Ebert, Pesesky, De Almeida, O’Donnell, DeGottardi, Keitany, Lu, Vong, Elyanow, Fields, Al-Asadi, Greissl, Baldo, Semprini, Cerchione, Nicolini, Mazza, Delmonte, Dobbs, Laguna-Goya, Carreño-Tarragona, Barrio, Imberti, Sottini, Quiros-Roldan, Rossi, Biondi, Bettini, D’Angio, Bonfanti, Tompkins, Alba, Dalgard, Sambri, Martinelli, Goldman, Heath, Su, Notarangelo, Paz-Artal, Martinez-Lopez, Howie, Carlson and Robins.