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.;Kedzierska, Katherine

Denise Doolan

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.

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Proceedings of the National Academy of Sciences of the United States of America

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117

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1091-6490

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National Academy of Sciences

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DOI

10.1073/pnas.2015486117