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

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.
Funding Information
  • Department of Health | National Health and Medical Research Council (1173871)