Suboptimal SARS-CoV-2-specific CD8(+) T cell response associated with the prominent HLA-A*02:01 phenotype

Habel, Jennifer H., Nguyen, Thi H.O., van de Sandt, Carolien E., Juno, Jennifer A., Chaurasia, Priyanka, Wragg, Kathleen, Koutsakos, Marios, Hensen, Luca, Jia, Xiaoxiao, Chua, Brendon, Zhang, Wuji, Tan, Hyon-Xhi, Flanagan, Katie L., Doolan, Denise L., Torresi, Joseph, Chen, Weisan, Wakim, Linda M., Cheng, Allen C., Doherty, Peter C., Petersen, Jan, Rossjohn, Jamie, Wheatley, Adam K., Kent, Stephen J., Rowntree, Louise C., and Kedzierska, Katherine (2020) Suboptimal SARS-CoV-2-specific CD8(+) T cell response associated with the prominent HLA-A*02:01 phenotype. Proceedings of the National Academy of Sciences of the United States of America, 117 (39). pp. 24384-24391.

[img]
Preview
PDF (Published Version) - Published Version
Available under License Creative Commons Attribution.

Download (1MB) | Preview
View at Publisher Website: https://doi.org/10.1073/pnas.2015486117
 
19
16


Abstract

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8(+) T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8(+) and CD4(+) T cells in vitro, with CD4(+) T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8(+) T cell epitopes, A2/S-269(-2)77 and A2/Orf1ab(3183-3191). Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S(269)(+)CD8(+) and A2/Orf1ab(3183)(+)CD8(+) populations indicated that A2/S(269)(+)CD8(+ )T cells were detected at comparable frequencies (similar to 1.3 x 10(-5)) in acute and convalescent HLA-A*02:01(+) patients. These frequencies were higher than those found in uninfected HLA-A*02:01(+) donors (similar to 2.5 x 10(-6)), but low when compared to frequencies for influenza-specific (A2/M1(58)) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (similar to 1.38 x 10(-4)) populations. Phenotyping A2/S(269)(+)CD8(+) T cells from COVID-19 convalescents ex vivo showed that A2/S(269)(+)CD8(+) T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8(+) T cells expressed granzymes and/or perforin. Furthermore, the bias toward naive, stem cell memory and central memory A2/S(269)(+)CD8(+) T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8(+) T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8(+) T cell immunity in COVID-19.

Item ID: 64895
Item Type: Article (Research - C1)
ISSN: 1091-6490
Keywords: CD8+T cells, COVID-19, HLA-A*02:01, SARS-CoV-2 epitopes
Copyright Information: This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Funders: Clifford Craig Foundation (CCF), National Health and Medical Research Council (NHMRC), Research Grants Council of the Hong Kong Special Administrative Region (RGC), Victorian Government (VG), Medical Research Future Fund (MRFF), Australian Research Council (ARC), University of Melbourne (UM), European Union (EU)
Projects and Grants: NHMRC Leadership Investigator Grant 1173871, NHMRC program grant 1132975, RGC Grant T11-712/19-N, MRFF Award 2002073, MRFF Award 1202445, NHMRC Program Grant 1149990, NHMRC Project Grant 1162760, NHMRC Career Development Fellowship 1140509, NHMRC Senior Research Fellowsihp 1102792, NHMRC Principal Research Fellowship 1137285, NHMRC Senior Principal Research Fellowship 1136322, ARC Laureate Fellowship, UM Melbourne Research Scholarship, EU Horizon 2020 Research and Innovation Program, UM International Research Scholarship, UM International Fee Remission Scholarship, NHMRC Early Career Fellowship 1123673, UM Melbourne Research Scholarship
Date Deposited: 28 Oct 2020 07:39
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3207 Medical microbiology > 320705 Medical virology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 50%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 100%
Downloads: Total: 16
Last 12 Months: 11
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page