HLA-B*15:01-positive severe COVID-19 patients lack CD8 + T cell pools with highly expanded public clonotypes
- Louise C. Rowntree
- Lilith F. Allen
- Ruth R. Hagen
- Hayley A. McQuilten
- Ahmed A. Quadeer
- Priyanka Chaurasia
- Prathanporn Kaewpreedee
- Kelly W. K. Lee
- Carolyn A. Cohen
- Jan Petersen
- Dene R. Littler
- Jennifer R. Habel
- Wuji Zhang
- Samuel M. S. Cheng
- Ken Ka Pang Chan
- Janette S. Y. Kwok
- Kathy S. M. Leung
- Joseph T. Wu
- Cheuk-Kwong Lee
- Jane Davies
- Pia S. Pannaraj
- E. Kaity Allen
- Paul G. Thomas
- Shidan Tosif
- Nigel W. Crawford
- Martha Lappas
- Irani Thevarajan
- Sharon R. Lewin
- Stephen J. Kent
- Jennifer A. Juno
- Katherine A. Bond
- Deborah A. Williamson
- Natasha E. Holmes
- Olivia C. Smibert
- Claire L. Gordon
- Jason A. Trubiano
- Tom C. Kotsimbos
- Allen C. Cheng
- Claudia Efstathiou
- Lance Turtle
- Ryan S. Thwaites
- Christopher E. Brightling
- Jamie Rossjohn
- Matthew R. McKay
- Jinmin Tian
- William Jun Liu
- George Fu Gao
- Jianqing Xu
- Kyuto Sonehara
- Ken J. Ishii
2025-09-02
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 S 919-927 peptide (B15/S 919 + 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/S 919 + 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/S 919 + 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/S 919 + CD8 + T-cell responses lacking a highly expanded key public B15/S 919 + CD8 + T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S 919 + 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/S 919 + CD8 + T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S 919 + CD8 + T-cells did not differ across disease severity. Moreover, B15/S 919 + 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.