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

Habel, Jennifer R.; 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

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/S(269)(+)CD8(+) and A2/Orf1ab(3183)(+)CD8(+) populations indicated that A2/S(269)(+)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/M1(58)) and Epstein–Barr virus (EBV)-specific (A2/BMLF(1280)) (∼1.38 × 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 naïve, 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.