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 if we are to optimize therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8 + T-cell memory to shared peptides presented by common HLA types like HLA-A2. Following re-infection, cross-reactive CD8 + T-cells enhance recovery and diminish clinical severity. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from SARS-CoV-2 Spike, Nucleocapsid and Membrane proteins led to the clonal expansion of SARS-CoV-2-specific CD8 + and CD4 + T-cells in vitro , with CD4 + sets being typically robust. For CD8 + T-cells taken directly ex vivo , we identified two HLA-A*02:01-restricted SARS-CoV-2 epitopes, A2/S 269–277 and A2/Orf1ab 3183–3191 . Using peptide-HLA tetramer enrichment, direct ex vivo assessment of the A2/S 269 + CD8 + and A2/Orf1ab 3183 + CD8 + populations indicated that the more prominent A2/S 269 + CD8 + set was detected at comparable frequency (∼1.3×10 −5 ) in acute and convalescent HLA-A*02:01 + patients. But, while the numbers were higher than those found in uninfected HLA-A*02:01 + donors (∼ 2.5×10 −6 ), they were low when compared with frequencies for influenza-specific (A2/M1 58 ) and EBV-specific (A2/BMLF 1280 ) (∼ 1.38×10 −4 ) populations. Phenotypic analysis ex vivo of A2/S 269 + CD8 + T-cells from COVID-19 convalescents showed that A2/S 269 + CD8 + T-cells were predominantly negative for the CD38, HLA-DR, PD-1 and CD71 activation markers, although the majority of total CD8 + T-cells were granzyme and/or perforin-positive. Furthermore, the bias towards naïve, stem cell memory and central memory A2/S 269 + CD8 + T-cells rather than effector memory populations suggests that SARS-CoV2 infection may be compromising CD8 + T-cell activation. Priming with an appropriate vaccine may thus have great value for optimizing protective CD8 + T-cell immunity in COVID-19.