Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease. Nature cardiovascular research Zhao, T. V., Hu, Z., Ohtsuki, S., Jin, K., Wu, B., Berry, G. J., Frye, R. L., Goronzy, J. J., Weyand, C. M. 2022; 1 (7): 634-648


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