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

Habel, J. R.; Nguyen, T. H. O.; van de Sandt, C. E.; Juno, J. A.; Chaurasia, P.; Wragg, K.; Koutsakos, M.; Hensen, L.; Chua, B.; Zhang, W.; Tan, H. X.; Flanagan, K. L.; Doolan, D.; Torresi, J.; Chen, W.; Wakim, L.; Cheng, A.; Petersen, J.; Rossjohn, J.; Wheatley, A. K.; Kent, S.; Rowntree, L.; Kedzierska, K.

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/S269-277 and A2/Orf1ab3183-3191. Using peptide-HLA tetramer enrichment, direct ex vivo assessment of the A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that the more prominent A2/S269+CD8+ set was detected at comparable frequency (1.3x10-5) 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 (2.5x10-6), they were low when compared with frequencies for influenza-specific (A2/M158) and EBV-specific (A2/BMLF1280) (1.38x10-4) populations. Phenotypic analysis ex vivo of A2/S269+CD8+ T-cells from COVID-19 convalescents showed that A2/S269+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 naive, stem cell memory and central memory A2/S269+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.