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; Stephanie Gras; J H Frederik Falkenburg; Mirjam H M Heemskerk

doi:10.7554/eLife.82050

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

Elife. 2022 Nov 21:11:e82050. doi: 10.7554/eLife.82050.

Affiliations

¹ Department of Hematology, Leiden University Medical Center, Leiden, Netherlands.
² Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.
³ Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands.
⁴ Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia.
⁵ Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.

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.

Keywords: CMV; SARS-CoV-2; T cells; cross-reactivity; heterologous immunity; human; immunology; inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
COVID-19*
Cytomegalovirus
Cytomegalovirus Infections*
Humans
Leukocytes, Mononuclear
Receptors, Antigen, T-Cell
SARS-CoV-2

Substances

Receptors, Antigen, T-Cell

Associated data

NTR/NL8589