SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells
Cilia R. Pothast, Romy C. Dijkland, Melissa Thaler, Renate S. Hagedoorn, Michel G.D. Kester, Anne K. Wouters, Pieter S. Hiemstra, Martijn J. van Hemert, Stéphanie Gras, JH Frederik Falkenburg, Mirjam H.M. Heemskerk
Abstract
Detection of severe acute respiratory syndrome 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 relatively high frequency and prevalence of cross-reactive T cells, we hypothesized cytomegalovirus (CMV) may induce these cross-reactive T cells. Stimulation of pre-pandemic cryo-preserved peripheral blood mononuclear cells (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.