HLA-B*15:01-positive severe COVID-19 patients lack CD8+ T cell pools with highly expanded public clonotypes, 2025, Rowntree et al.

SNT Gatchaman

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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; null, null; 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

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.

SIGNIFICANCE
Understanding factors driving asymptomatic versus severe disease is of key importance if we are to control emerging and re-emerging viral infections. As preexisting CD8+ T-cell responses have been associated with asymptomatic COVID-19 in individuals expressing HLA-B*15:01, comparing to mild disease, we defined cross-reactive CD8+ T-cells responses directed at the HLA-B*15:01/S919 epitope in COVID-19 patients across disease outcomes ranging from asymptomatic to critical illness. We found that severe COVID-19 patients had an enrichment of an alternate T-cell receptor (TCR) motif compared to the key public motif expanded in milder patients. Our study provides evidence on differential nature of TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe/critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.

Web | PDF | Proceedings of the National Academy of Sciences | Open Access
 
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