Pre-existent cardiovascular disease is a risk factor for weak anti-viral immunity, but underlying mechanisms remain undefined. Here, we report that patients with coronary artery disease (CAD) have macrophages (M?) that actively suppress the induction of helper T cells reactive to two viral antigens: the SARS-CoV2 Spike protein and the Epstein-Barr virus (EBV) glycoprotein 350. CAD M? overexpressed the methyltransferase METTL3, promoting the accumulation of N6-methyladenosine (m6A) in Poliovirus receptor (CD155) mRNA. m6A modifications of positions 1635 and 3103 in the 3'UTR of CD155 mRNA stabilized the transcript and enhanced CD155 surface expression. As a result, the patients' M? abundantly expressed the immunoinhibitory ligand CD155 and delivered negative signals to CD4+ T cells expressing CD96 and/or TIGIT receptors. Compromised antigen-presenting function of METTL3hi CD155hi M? diminished anti-viral T cell responses in vitro and in vivo. LDL and its oxidized form induced the immunosuppressive M? phenotype. Undifferentiated CAD monocytes had hypermethylated CD155 mRNA, implicating post-transcriptional RNA modifications in the bone-marrow in shaping anti-viral immunity in CAD.
View details for DOI 10.1038/s44161-022-00096-8
View details for PubMedID 36860353