Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease
Tuantuan Zhao, Zhao‐Lan Hu, Shozo Ohtsuki, Ke Jin, Bowen Wu, Gerald J. Berry, Robert L. Frye, Jörg J. Goronzy, Cornelia M. Weyand
Abstract
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 N6-methyladenosine (m6A) in poliovirus receptor (PVR) mRNA. m6A 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 METTL3hiCD155hi 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. Zhao et al. show that, in patients with coronary artery disease, CD4+ T cells present a blunted response to SARS-CoV-2 and Epstein–Barr viral antigens, due to the overexpression of the immune checkpoint CD155 in macrophages, primed by the exposure to low-density lipoprotein and its oxidized form. The experiments show that CD155 overexpression is due to stabilizing post-translational modifications mediated by the mRNA methylase MTTL3.