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

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.

Prepandemic cross-reactive humoral immunity to SARS-CoV-2 in Africa: Systematic review and meta-analysis

“…Cross-reactive clusters of differentiation 4+ and clusters of differentiation 8+ T-cell responses to SARS-CoV-2 were documented in 90% of prepandemic samples from Uganda [25] , but only 10-50% in prepandemic samples from the USA or Europe [26] , [27] , [28] . Cross-reactive T-cell responses may derive from both homologous pathogens (other coronaviruses, including the four globally-distributed coronaviruses or other coronaviruses with country distribution largely overlapping with malaria burden [20] ) and non-homologous ones (e.g., cytomegalovirus) [29] .…”

A distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

“…Bacher and colleagues demonstrated that in previously SARS-CoV-2-unexposed individuals with COVID-19, pre-existing SARS-CoV-2-reactive circulating T cells possessed low TCR avidity and were enriched in patients with more severe disease, arguing against a protective function for cross-reative T cells (49). Furthermore, cross-reactivity might not only be limited to human coronaviruses (46, 49), and others have shown that microbial peptides from commensal bacteria and other viruses are potential sources of heterologous immunity to SARS-CoV-2 (68, 69). Here, we predicted that TCRs specific for immunodominant SARS-CoV-2 peptides in our dataset cross-react with other human coronaviruses.…”

Proinflammatory impact of putative viral-specific CD8+ T cells infiltrating new-onset seropositive rheumatoid arthritis synovium

“…Furthermore, 0.23% of the CD3 + TCR + population in PB was contained in putative MHC class II-restricted CDR3α or CDR3β virus-reactive CD4 + T cells. Since there were no matches to a CDR3α/β pair from the VDJdb, some of these TCR may not be specific for the same published viral epitope and may cross-react with other viruses 62 . Due to the paired study design, in both PB and ST of donor 4 we identified a clonotype matching a known CMV-reactive CDR3β, which we validated by tetramer staining in PB.…”