SARS-CoV-2-specific CD8+ T cells from people with long COVID establish and maintain effector phenotype and key TCR signatures over 2 years

Rowntree, Louise C., Audsley, Jennifer, Allen, Lilith F., McQuilten, Hayley A., Hagen, Ruth R., Chaurasia, Priyanka, Petersen, Jan, Littler, Dene R., Tan, Hyon-Xhi, Murdiyarso, Lydia, Habel, Jennifer R., Foo, Isabelle J. H., Zhang, Wuji, ten Berge, Elizabeth R. V., Ganesh, Hanujah, Kaewpreedee, Prathanporn, Lee, Kelly W. K., Cheng, Samuel M. S., Kwok, Janette S. Y., Jayasinghe, Dhilshan, Gras, Stephanie, Juno, Jennifer A., Wheatley, Adam K., Kent, Stephen J., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Cheng, Allen C., Kotsimbos, Tom C., Trubiano, Jason A., Holmes, Natasha E., Pang Chan, Ken Ka, Hui, David S. C., Peiris, Malik, Poon, Leo L. M., Lewin, Sharon R., Doherty, Peter C., Thevarajan, Irani, Valkenburg, Sophie A., Kedzierska, Katherine and Nguyen, Thi H. O. 2024. SARS-CoV-2-specific CD8+ T cells from people with long COVID establish and maintain effector phenotype and key TCR signatures over 2 years. Proceedings of the National Academy of Sciences 121 (39) , e2411428121. 10.1073/pnas.2411428121

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	28 October 2024
Date of Acceptance:	23 July 2024
Last Modified:	29 Oct 2024 13:45
URI:	https://orca.cardiff.ac.uk/id/eprint/173460

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