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

Rowntree, LC; Allen, LF; Hagen, RR; McQuilten, HA; Quadeer, AA; Chaurasia, P; Kaewpreedee, P; Lee, KWK; Cohen, CA; Petersen, J; Littler, DR; Habel, JR; Zhang, W; Cheng, SMS; Chan, KKP; Kwok, JSY; Leung, KSM; Wu, JT; Lee, CK; Davies, J; Pannaraj, PS; Allen, EK; Thomas, PG; Tosif, S; Crawford, NW; Lappas, M; Thevarajan, I; Lewin, SR; Kent, SJ; Juno, JA; Bond, KA; Williamson, DA; Holmes, NE; Smibert, OC; Gordon, CL; Trubiano, JA; Kotsimbos, TC; Cheng, AC; Efstathiou, C; Turtle, L; Thwaites, RS; Brightling, CE; PHOSP- COVID Collaborative Group; Rossjohn, J; McKay, MR; Tian, J; Liu, WJ; Gao, GF; Xu, J; Sonehara, K; Ishii, KJ; Namkoong, H; Okada, Y; Peiris, M; Hui, DSC; Poon, LLM; Doherty, PC; Nguyen, THO; Valkenburg, SA; Kedzierska, K

Author(s): Rowntree, LC; Allen, LF; Hagen, RR; McQuilten, HA; Quadeer, AA; Chaurasia, P; Kaewpreedee, P; Lee, KWK; Cohen, CA; Petersen, J; Littler, DR; Habel, JR; Zhang, W; Cheng, SMS; Chan, KKP; Kwok, JSY; Leung, KSM; Wu, JT; Lee, CK; Davies, J; Pannaraj, PS; Allen, EK; Thomas, PG; Tosif, S; Crawford, NW; Lappas, M; Thevarajan, I; Lewin, SR; Kent, SJ; Juno, JA; Bond, KA; Williamson, DA; Holmes, NE; Smibert, OC; Gordon, CL; Trubiano, JA; Kotsimbos, TC; Cheng, AC; Efstathiou, C; Turtle, L; Thwaites, RS; Brightling, CE; PHOSP- COVID Collaborative Group; Rossjohn, J; McKay, MR; Tian, J; Liu, WJ; Gao, GF; Xu, J; Sonehara, K; Ishii, KJ; Namkoong, H; Okada, Y; Peiris, M; Hui, DSC; Poon, LLM; Doherty, PC; Nguyen, THO; Valkenburg, SA; Kedzierska, K;
Details: Publication Year 2025-09-09,Volume 122,Issue #36,Page e2503145122
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Research article
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 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.
Publisher: American Association for the Advancement of Science
Keywords: Humans; *COVID-19/immunology/genetics; *CD8-Positive T-Lymphocytes/immunology; *SARS-CoV-2/immunology; Male; Female; Middle Aged; Adult; Aged; Spike Glycoprotein, Coronavirus/immunology; CD8+ T cells; Covid-19; Hla-b*15:01; T cell receptors; severe disease
Department(s): Infectious Diseases
Publisher's Version: https://doi.org/10.1073/pnas.2503145122
Open Access at Publisher's Site: https://doi.org/10.1073/pnas.2503145122
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-10-23 05:42:30

Last Modified: 2025-10-23 05:42:43