SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells

Pothast, C. R.; Dijkland, R. C.; Thaler, M.; Hagedoorn, R. S.; Kester, M. G.; Wouters, A. K.; Hiemstra, P. S.; van Hemert, M. J.; Gras, S.; Falkenburg, J. F.; Heemskerk, M. H.

doi:10.1101/2022.07.31.502203

bioRxiv · 10.1101/2022.07.31.502203

SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells

Pothast, C. R.·Dijkland, R. C.·Thaler, M.·Hagedoorn, R. S.·Kester, M. G.·Wouters, A. K.·Hiemstra, P. S.·van Hemert, M. J.·Gras, S.·Falkenburg, J. F.·Heemskerk, M. H.

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Abstract

Detection of SARS-coronavirus-2 (SARS-CoV-2) specific CD4+ and CD8+ T cells in SARS-CoV-2-unexposed donors has been explained by the presence of T cells primed by other coronaviruses. However, based on the relative high frequency and prevalence of cross-reactive T cells, we hypothesized CMV may induce these cross-reactive T cells. Stimulation of pre-pandemic cryo-preserved PBMCs with SARS-CoV-2 peptides revealed that frequencies of SARS-CoV-2-specific T cells were higher in CMV-seropositive donors. Characterization of these T cells demonstrated that membrane-specific CD4+ and spike-specific CD8+ T cells originate from cross-reactive CMV-specific T cells. Spike-specific CD8+ T cells recognize SARS-CoV-2 spike peptide FVSNGTHWF (FVS) and dissimilar CMV pp65 peptide IPSINVHHY (IPS) presented by HLA-B*35:01. These dual IPS/FVS-reactive CD8+ T cells were found in multiple donors as well as severe COVID-19 patients and shared a common T cell receptor (TCR), illustrating that IPS/FVS-cross-reactivity is caused by a public TCR. In conclusion, CMV-specific T cells cross-react with SARS-CoV-2, despite low sequence homology between the two viruses, and may contribute to the pre-existing immunity against SARS-CoV-2.

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Pothast, C. R., Dijkland, R. C., Thaler, M., Hagedoorn, R. S., Kester, M. G., Wouters, A. K., Hiemstra, P. S., van Hemert, M. J., Gras, S., Falkenburg, J. F., Heemskerk, M. H.. 2022-08-01. SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells. https://doi.org/10.1101/2022.07.31.502203

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