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_269–277 and A2/Orf1ab_3183–3191. 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.

加深对 COVID-19 中人类 T 细胞介导的免疫的了解对于优化治疗和疫苗策略非常重要。流感经验表明，感染会启动 CD8 ⁺ T 细胞对常见 HLA 类型（如 HLA-A2）呈递的肽的记忆，从而增强恢复并减轻再次感染时的临床严重程度。用严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的重叠肽刺激 COVID-19 恢复期患者的外周血单核细胞，导致 SARS-CoV-2 特异性 CD8 ⁺和 CD4 ⁺ T 细胞在体外克隆扩增，CD4 ⁺ T 细胞很强大。我们鉴定了两个 HLA-A*02:01 限制性 SARS-CoV-2 特异性 CD8 ⁺ T 细胞表位，A2/S _269–277和 A2/Orf1ab _3183–3191 。使用肽-HLA四聚体富集，对 A2/S ₂₆₉ ⁺ CD8 ⁺和 A2/Orf1ab ₃₁₈₃ ⁺ CD8 ⁺群体进行直接离体评估表明，以相当的频率检测到 A2/S ₂₆₉ ⁺ CD8 ⁺ T 细胞 (∼1.3 × 10 ^{− 5} ) 在急性和恢复期 HLA-A*02:01 ⁺患者中。这些频率高于未感染的 HLA-A*02:01 ⁺供体 (∼2.5 × 10 ^-6 ) 中发现的频率，但与流感特异性 (A2/M1 ₅₈ ) 和 Epstein-Barr 病毒 (EBV) 的频率相比较低) 特定 (A2/BMLF ₁₂₈₀ ) (∼1.38 × 10 ^-4 ) 群体。 对来自 COVID-19 康复者的 A2/S ₂₆₉ ⁺ CD8 ⁺ T 细胞进行离体表型分析表明，A2/S ₂₆₉ ⁺ CD8 ⁺ T 细胞的 CD38、HLA-DR、PD-1 和 CD71 激活标记物主要呈阴性，尽管大多数表达颗粒酶和/或穿孔素的总 CD8 ⁺ T 细胞。此外，偏向幼稚、干细胞记忆和中央记忆 A2/S ₂₆₉ ⁺ CD8 ⁺ T 细胞而不是效应记忆群体表明 SARS-CoV-2 感染可能会损害 CD8 ⁺ T 细胞的激活。因此，接种适当的疫苗可能有利于优化 COVID-19 中的 CD8 ⁺ T 细胞免疫。