SARS-CoV-2-specific CD8+ T cells from people with long COVID establish and maintain effector phenotype and key TCR signatures over 2 years
Citation
Louise C Rowntree, Jennifer Audsley, Lilith F Allen, Hayley A McQuilten, Ruth R Hagen, Priyanka Chaurasia, Jan Petersen, Dene R Littler, Hyon-Xhi Tan, Lydia Murdiyarso, Jennifer R Habel, Isabelle J H Foo, Wuji Zhang, Elizabeth R V Ten Berge, Hanujah Ganesh, Prathanporn Kaewpreedee, Kelly W K Lee, Samuel M S Cheng, Janette S Y Kwok, Dhilshan Jayasinghe, Stephanie Gras, Jennifer A Juno, Adam K Wheatley, Stephen J Kent, Jamie Rossjohn, Allen C Cheng, Tom C Kotsimbos, Jason A Trubiano, Natasha E Holmes, Ken Ka Pang Chan, David S C Hui, Malik Peiris, Leo L M Poon, Sharon R Lewin, Peter C Doherty, Irani Thevarajan, Sophie A Valkenburg, Katherine Kedzierska, Thi H O Nguyen
PNAS, September 16, 2024, 121 (39) e2411428121. DOI: https://doi.org/10.1073/pnas.2411428121
Abstract
Significance
Abstract
Long COVID occurs in a small but important minority of patients following COVID-19, reducing quality of life and contributing to healthcare burden. Although research into underlying mechanisms is evolving, immunity is understudied. SARS-CoV-2-specific T cell responses are of key importance for viral clearance and COVID-19 recovery. However, in long COVID, the establishment and persistence of SARS-CoV-2-specific T cells are far from clear, especially beyond 12 mo postinfection and postvaccination. We defined ex vivo antigen-specific B cell and T cell responses and their T cell receptors (TCR) repertoires across 2 y postinfection in people with long COVID. Using 13 SARS-CoV-2 peptide–HLA tetramers, spanning 11 HLA allotypes, as well as spike and nucleocapsid probes, we tracked SARS-CoV-2-specific CD8+ and CD4+ T cells and B-cells in individuals from their first SARS-CoV-2 infection through primary vaccination over 24 mo. The frequencies of ORF1a- and nucleocapsid-specific T cells and B cells remained stable over 24 mo. Spike-specific CD8+ and CD4+ T cells and B cells were boosted by SARS-CoV-2 vaccination, indicating immunization, in fully recovered and people with long COVID, altered the immunodominance hierarchy of SARS-CoV-2 T cell epitopes. Meanwhile, influenza-specific CD8+ T cells were stable across 24 mo, suggesting no bystander-activation. Compared to total T cell populations, SARS-CoV-2-specific T cells were enriched for central memory phenotype, although the proportion of central memory T cells decreased following acute illness. Importantly, TCR repertoire composition was maintained throughout long COVID, including postvaccination, to 2 y postinfection. Overall, we defined ex vivo SARS-CoV-2-specific B cells and T cells to understand primary and recall responses, providing key insights into antigen-specific responses in people with long COVID.