HLA-B*15:01-positive severe COVID-19 patients lack CD8 + T cell pools with highly expanded public clonotypes

Rowntree, Louise C., Allen, Lilith F., Hagen, Ruth R., McQuilten, Hayley A., Quadeer, Ahmed A., Chaurasia, Priyanka, Kaewpreedee, Prathanporn, Lee, Kelly W. K., Cohen, Carolyn A., Petersen, Jan, Littler, Dene R., Habel, Jennifer R., Zhang, Wuji, Cheng, Samuel M. S., Chan, Ken Ka Pang, Kwok, Janette S. Y., Leung, Kathy S. M., Wu, Joseph T., Lee, Cheuk-Kwong, Davies, Jane, Pannaraj, Pia S., Kaity Allen, E., Thomas, Paul G., Tosif, Shidan, Crawford, Nigel W., Lappas, Martha, Thevarajan, Irani, Lewin, Sharon R., Kent, Stephen J., Juno, Jennifer A., Bond, Katherine A., Williamson, Deborah A., Holmes, Natasha E., Smibert, Olivia C., Gordon, Claire L., Trubiano, Jason A., Kotsimbos, Tom C., Cheng, Allen C., Efstathiou, Claudia, Turtle, Lance, Thwaites, Ryan S., Brightling, Christopher E., PHOSP-COVID Collaborative Group, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, McKay, Matthew R., Tian, Jinmin, Liu, William Jun, Gao, George Fu, Xu, Jianqing, Sonehara, Kyuto, Ishii, Ken J., Namkoong, Ho, Okada, Yukinori, Peiris, Malik, Hui, David S. C., Poon, Leo L. M., Doherty, Peter C., Nguyen, Thi H. O., Valkenburg, Sophie A. and Kedzierska, Katherine 2025. HLA-B*15:01-positive severe COVID-19 patients lack CD8 + T cell pools with highly expanded public clonotypes. Proceedings of the National Academy of Sciences 122 (36) , e2503145122. 10.1073/pnas.2503145122

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Abstract

Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8+ T-cells directed against HLA-B*15:01-restricted Spike-derived S919-927 peptide (B15/S919+CD8+ T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8+ T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S919+CD8+ T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S919+CD8+ T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S919+CD8+ T-cell responses lacking a highly expanded key public B15/S919+CD8+ T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S919+CD8+ T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S919+CD8+ T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S919+CD8+ T-cells did not differ across disease severity. Moreover, B15/S919+CD8+ T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	10 September 2025
Date of Acceptance:	31 July 2025
Last Modified:	10 Sep 2025 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/181026

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