Proceedings of the National Academy of Sciences of the United States of America · 2025
HLA-B*15:01-positive severe COVID-19 patients lack CD8+ T cell pools with highly expanded public clonotypes.
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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, 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, Kedzierska Katherine
Аннотация
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.