Patients with coronary artery disease have suppressed antiviral immunity due to hyperactivity of the immunological checkpoint CD155

Weak anti-viral immunity is associated with pre-existing cardiovascular illness, but the underlying mechanisms are yet unknown. In the current study, we show that Macrophages (M) in patients with Coronary Artery Disease (CAD) actively suppress the induction of helper T cells that are reactive to two viral antigens: the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the Epstein-Barr Virus (EBV) glycoprotein 350. The methyltransferase METTL3 was overexpressed by CAD M, which caused N6-methyladenosine (m6A) to build up in the Polio Virus Receptor (PVR) mRNA. The PVR mRNA's 3′ untranslated region had m6A alterations at locations 1635 and 3103 that stabilised the transcript and improved surface expression of the PVR-encoded CD155. Due to the patients' M's high expression of the immunoinhibitory ligand CD155, CD4+ T cells expressing CD96 and/or TIGIT receptors received unfavourable signals from the M. Reduced anti-viral T cell responses in vitro and in vivo were caused by METTL3hiCD155hi M's compromised antigen-presenting activity. The immunosuppressive M phenotype was brought on by low-density lipoprotein and its oxidised form.