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.

Journal

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

Publication Name

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

Volume

117

ISBN/ISSN

1091-6490

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Publisher

National Academy of Sciences

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DOI

10.1073/pnas.2015486117