Distinct CD8+ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+ Patients

Masuda, K.; Iketani, S.; Liu, L.; Huang, J.; Qiao, Y.; Shah, J.; McNairy, M. L.; Groso, C.; Ricupero, C.; Loffredo, L. F.; Wang, Q.; Purpura, L.; Coelho-dos-Reis, J. G. A.; Sheng, Z.; Yin, M. T.; Tsuji, M.

doi:10.1101/2025.01.12.632164

bioRxiv · 10.1101/2025.01.12.632164

Distinct CD8+ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+ Patients

Masuda, K.·Iketani, S.·Liu, L.·Huang, J.·Qiao, Y.·Shah, J.·McNairy, M. L.·Groso, C.·Ricupero, C.·Loffredo, L. F.·Wang, Q.·Purpura, L.·Coelho-dos-Reis, J. G. A.·Sheng, Z.·Yin, M. T.·Tsuji, M.

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Abstract

Although emerging data have revealed the critical role of memory CD8+ T cells in preventing and controlling SARS-CoV-2 infection, virus-specific CD8+ T-cell responses against SARS-CoV-2 and its memory and innate-like subsets in unvaccinated COVID-19 patients with various disease manifestations in an HLA-restricted fashion remain to be understood. Here, we show the strong association of protective cellular immunity with mild COVID-19 and unique cell types against SARS-CoV-2 virus in an HLA-A2 restricted manner. ELISpot assays reveal that SARS-CoV-2-specific CD8+ T-cell responses in mild COVID-19 patients are significantly higher than in severe patients, whereas neutralizing antibody responses against SARS-CoV-2 virus significantly correlate with disease severity. Single-cell analyses of HLA-A2-restricted CD8+ T cells, which recognize highly conserved immunodominant SARS-CoV-2-specific epitopes, demonstrate divergent profiles in unvaccinated patients with mild versus severe disease. CD8+ T-cell types including cytotoxic KLRB1+ CD8 cells with innate-like T-cell signatures, IFNGhiID3hi memory cells and IL7R+ proliferative stem cell-like memory cells are preferentially observed in mild COVID-19, whereas distinct terminally-differentiated T-cell subsets are predominantly detected in severe COVID-19: highly activated FASLhi T-cell subsets and early-terminated or dysfunctional IL4R+ GATA3+ stem cell-like memory T-cell subset. In conclusion, our findings suggest that unique and contrasting SARS-CoV-2-specific CD8+ T-cell profiles may dictate COVID-19 severity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/632164v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@154796corg.highwire.dtl.DTLVardef@efca24org.highwire.dtl.DTLVardef@c01b9corg.highwire.dtl.DTLVardef@54ad83_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO SARS-CoV-2 epitope-specific CD8+ T-cell subtypes associated with mild or severe COVID-19 patients. Potent memory CD8+ T-cell subtypes with gene signature in mild COVID-19 patients (upper) and dysfunctional CD8+ T-cell subtypes with gene signature in severe COVID-19 patients (lower). C_FIG

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Masuda, K., Iketani, S., Liu, L., Huang, J., Qiao, Y., Shah, J., McNairy, M. L., Groso, C., Ricupero, C., Loffredo, L. F., Wang, Q., Purpura, L., Coelho-dos-Reis, J. G. A., Sheng, Z., Yin, M. T., Tsuji, M.. 2025-01-14. Distinct CD8+ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+ Patients. https://doi.org/10.1101/2025.01.12.632164

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