Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease

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 (Mϕ) that actively suppress the induction of helper T cells 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. CAD Mϕ overexpressed the methyltransferase METTL3, promoting the accumulation of N 6 -methyladenosine (m 6 A) in poliovirus receptor ( PVR ) mRNA. m 6 A modifications of positions 1635 and 3103 in the 3′ untranslated region of PVR mRNA stabilized the transcript and enhanced surface expression of PVR -encoded CD155. As a result, the patients’ Mϕ 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 METTL3 hi CD155 hi Mϕ diminished anti-viral T cell responses in vitro and in vivo. Low-density lipoprotein and its oxidized form induced the immunosuppressive Mϕ phenotype. Undifferentiated CAD monocytes had hypermethylated PVR mRNA, implicating post-transcriptional RNA modifications in the bone marrow in shaping anti-viral immunity in CAD.