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

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/ S₂₆₉-₂₇₇ and A2/Orf1ab₃₁₈₃-3191. Using peptide−HLA tetramer enrichment, direct ex vivo assessment of A2/S₂₆₉⁺CD8⁺ and A2/ Orf1ab₃₁₈₃⁺CD8⁺ populations indicated that A2/S₂₆₉⁺CD8⁺ T cells were detected at comparable frequencies (∼1.3 × 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 (∼2.5 × 10⁻⁶), but low when compared to frequencies for influenza-specific (A2/M1₅₈) and Epstein-Barr virus (EBV)-specific (A2/BMLF₁₂₈₀) (∼1.38 × 10⁻⁴) populations. Phenotyping A2/S₂₆₉⁺CD8⁺ T cells from COVID-19 convalescents ex vivo showed that A2/S₂₆₉⁺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 naïve, stem cell memory and central memory A2/S₂₆₉⁺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.