tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2025 Sep 9;122(36):e2503145122.
doi: 10.1073/pnas.2503145122. Epub 2025 Sep 2. HLA-B*15:01-positive severe COVID-19 patients lack CD8[SUP]+[/SUP] T cell pools with highly expanded public clonotypes
Louise C Rowntree[SUP] 1 [/SUP], Lilith F Allen[SUP] 1 [/SUP], Ruth R Hagen[SUP] 1 [/SUP], Hayley A McQuilten[SUP] 1 [/SUP], Ahmed A Quadeer[SUP] 2 3 [/SUP], Priyanka Chaurasia[SUP] 4 [/SUP], Prathanporn Kaewpreedee[SUP] 5 [/SUP], Kelly W K Lee[SUP] 5 [/SUP], Carolyn A Cohen[SUP] 5 [/SUP], Jan Petersen[SUP] 4 [/SUP], Dene R Littler[SUP] 4 [/SUP], Jennifer R Habel[SUP] 1 [/SUP], Wuji Zhang[SUP] 1 [/SUP], Samuel M S Cheng[SUP] 6 [/SUP], Ken Ka Pang Chan[SUP] 7 8 [/SUP], Janette S Y Kwok[SUP] 9 [/SUP], Kathy S M Leung[SUP] 10 11 12 13 [/SUP], Joseph T Wu[SUP] 10 11 12 13 [/SUP], Cheuk-Kwong Lee[SUP] 10 11 12 13 [/SUP], Jane Davies[SUP] 14 [/SUP], Pia S Pannaraj[SUP] 15 16 [/SUP], E Kaity Allen[SUP] 17 [/SUP], Paul G Thomas[SUP] 17 [/SUP], Shidan Tosif[SUP] 18 19 20 [/SUP], Nigel W Crawford[SUP] 18 19 20 21 [/SUP], Martha Lappas[SUP] 22 [/SUP], Irani Thevarajan[SUP] 23 24 [/SUP], Sharon R Lewin[SUP] 23 24 25 [/SUP], Stephen J Kent[SUP] 1 26 27 [/SUP], Jennifer A Juno[SUP] 1 [/SUP], Katherine A Bond[SUP] 1 28 29 [/SUP], Deborah A Williamson[SUP] 24 28 30 [/SUP], Natasha E Holmes[SUP] 23 31 32 33 [/SUP], Olivia C Smibert[SUP] 31 34 35 [/SUP], Claire L Gordon[SUP] 1 31 [/SUP], Jason A Trubiano[SUP] 23 33 34 35 [/SUP], Tom C Kotsimbos[SUP] 36 37 [/SUP], Allen C Cheng[SUP] 38 39 [/SUP], Claudia Efstathiou[SUP] 40 [/SUP], Lance Turtle[SUP] 41 [/SUP], Ryan S Thwaites[SUP] 40 [/SUP], Christopher E Brightling[SUP] 42 [/SUP]; PHOSP-COVID Collaborative Group; Jamie Rossjohn[SUP] 4 43 [/SUP], Matthew R McKay[SUP] 1 2 3 28 [/SUP], Jinmin Tian[SUP] 44 [/SUP], William Jun Liu[SUP] 44 [/SUP], George Fu Gao[SUP] 44 [/SUP], Jianqing Xu[SUP] 45 [/SUP], Kyuto Sonehara[SUP] 46 47 [/SUP], Ken J Ishii[SUP] 48 49 50 [/SUP], Ho Namkoong[SUP] 51 [/SUP], Yukinori Okada[SUP] 47 50 52 53 [/SUP], Malik Peiris[SUP] 5 6 54 [/SUP], David S C Hui[SUP] 7 8 [/SUP], Leo L M Poon[SUP] 5 6 54 [/SUP], Peter C Doherty[SUP] #[/SUP][SUP] 1 [/SUP], Thi H O Nguyen[SUP] #[/SUP][SUP] 1 [/SUP], Sophie A Valkenburg[SUP] #[/SUP][SUP] 1 5 [/SUP], Katherine Kedzierska[SUP] #[/SUP][SUP] 1 55 [/SUP]
Affiliations
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[SUP]+[/SUP] T-cells directed against HLA-B*15:01-restricted Spike-derived S[SUB]919-927[/SUB] peptide (B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8[SUP]+[/SUP] T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cell responses lacking a highly expanded key public B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cells did not differ across disease severity. Moreover, B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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.
Keywords: CD8+ T cells; COVID-19; HLA-B*15:01; T cell receptors; severe disease.
. 2025 Sep 9;122(36):e2503145122.
doi: 10.1073/pnas.2503145122. Epub 2025 Sep 2. HLA-B*15:01-positive severe COVID-19 patients lack CD8[SUP]+[/SUP] T cell pools with highly expanded public clonotypes
Louise C Rowntree[SUP] 1 [/SUP], Lilith F Allen[SUP] 1 [/SUP], Ruth R Hagen[SUP] 1 [/SUP], Hayley A McQuilten[SUP] 1 [/SUP], Ahmed A Quadeer[SUP] 2 3 [/SUP], Priyanka Chaurasia[SUP] 4 [/SUP], Prathanporn Kaewpreedee[SUP] 5 [/SUP], Kelly W K Lee[SUP] 5 [/SUP], Carolyn A Cohen[SUP] 5 [/SUP], Jan Petersen[SUP] 4 [/SUP], Dene R Littler[SUP] 4 [/SUP], Jennifer R Habel[SUP] 1 [/SUP], Wuji Zhang[SUP] 1 [/SUP], Samuel M S Cheng[SUP] 6 [/SUP], Ken Ka Pang Chan[SUP] 7 8 [/SUP], Janette S Y Kwok[SUP] 9 [/SUP], Kathy S M Leung[SUP] 10 11 12 13 [/SUP], Joseph T Wu[SUP] 10 11 12 13 [/SUP], Cheuk-Kwong Lee[SUP] 10 11 12 13 [/SUP], Jane Davies[SUP] 14 [/SUP], Pia S Pannaraj[SUP] 15 16 [/SUP], E Kaity Allen[SUP] 17 [/SUP], Paul G Thomas[SUP] 17 [/SUP], Shidan Tosif[SUP] 18 19 20 [/SUP], Nigel W Crawford[SUP] 18 19 20 21 [/SUP], Martha Lappas[SUP] 22 [/SUP], Irani Thevarajan[SUP] 23 24 [/SUP], Sharon R Lewin[SUP] 23 24 25 [/SUP], Stephen J Kent[SUP] 1 26 27 [/SUP], Jennifer A Juno[SUP] 1 [/SUP], Katherine A Bond[SUP] 1 28 29 [/SUP], Deborah A Williamson[SUP] 24 28 30 [/SUP], Natasha E Holmes[SUP] 23 31 32 33 [/SUP], Olivia C Smibert[SUP] 31 34 35 [/SUP], Claire L Gordon[SUP] 1 31 [/SUP], Jason A Trubiano[SUP] 23 33 34 35 [/SUP], Tom C Kotsimbos[SUP] 36 37 [/SUP], Allen C Cheng[SUP] 38 39 [/SUP], Claudia Efstathiou[SUP] 40 [/SUP], Lance Turtle[SUP] 41 [/SUP], Ryan S Thwaites[SUP] 40 [/SUP], Christopher E Brightling[SUP] 42 [/SUP]; PHOSP-COVID Collaborative Group; Jamie Rossjohn[SUP] 4 43 [/SUP], Matthew R McKay[SUP] 1 2 3 28 [/SUP], Jinmin Tian[SUP] 44 [/SUP], William Jun Liu[SUP] 44 [/SUP], George Fu Gao[SUP] 44 [/SUP], Jianqing Xu[SUP] 45 [/SUP], Kyuto Sonehara[SUP] 46 47 [/SUP], Ken J Ishii[SUP] 48 49 50 [/SUP], Ho Namkoong[SUP] 51 [/SUP], Yukinori Okada[SUP] 47 50 52 53 [/SUP], Malik Peiris[SUP] 5 6 54 [/SUP], David S C Hui[SUP] 7 8 [/SUP], Leo L M Poon[SUP] 5 6 54 [/SUP], Peter C Doherty[SUP] #[/SUP][SUP] 1 [/SUP], Thi H O Nguyen[SUP] #[/SUP][SUP] 1 [/SUP], Sophie A Valkenburg[SUP] #[/SUP][SUP] 1 5 [/SUP], Katherine Kedzierska[SUP] #[/SUP][SUP] 1 55 [/SUP]
Affiliations
- PMID: 40892914
- DOI: 10.1073/pnas.2503145122
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[SUP]+[/SUP] T-cells directed against HLA-B*15:01-restricted Spike-derived S[SUB]919-927[/SUB] peptide (B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8[SUP]+[/SUP] T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cell responses lacking a highly expanded key public B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] T-cells did not differ across disease severity. Moreover, B15/S[SUB]919[/SUB][SUP]+[/SUP]CD8[SUP]+[/SUP] 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.
Keywords: CD8+ T cells; COVID-19; HLA-B*15:01; T cell receptors; severe disease.