Integrative Omics Analysis Reveals a CD206 + Macrophage/Dendritic Cell–CD155–TIGIT + Regulatory T Cell Axis as a Protective Immune Checkpoint Pathway in Atherosclerosis Progression

ABSTRACT RNA sequencing (RNA‐seq) analysis revealed transcriptional features indicative of sustained immunosuppression within regulatory T cells (Tregs) isolated from atherosclerotic tissues, highlighting the critical contribution of immune checkpoint (ICP) receptor–ligand interactions to atherosclerosis progression. To comprehensively characterize the roles of ICP signaling in this context, we integrated transcriptomic profiling, quantitative RT‐PCR, and flow cytometry analysis, yielding several key findings: (1) Multiomics integration revealed global transcriptomic alterations in ICP receptors and ligands across diverse tissues, immune cell types, and disease stages in both human and murine models of atherosclerosis; (2) Several ICP components demonstrated functional relevance, including dual‐function ligand CD155 (PVR); inhibitory ligands Lgals3 and Itgb1; stimulatory ligands Tnfrsf9 and CD48; and inhibitory receptors Havcr2 and Lair1. These molecules act as microenvironmental sensors, dynamically responding to atherosclerotic cues; (3) Experimental validation confirmed upregulation of the CD155‐TIGIT axis within immune cells of atherosclerotic plaques. Notably, CD155 expression positively correlated with CD206 expression in both CD11b + CD11c + and CD11b − CD11c + cells, irrespective of tissue context; and (4) The CD206 + macrophages/DCs–CD155–TIGIT + Treg axis emerged as a potential ICP‐mediated pathway that confers immunoregulatory protection against atherosclerosis progression. Collectively, these findings uncover novel immunomodulatory roles for ICP ligands in atherosclerosis, expanding their known functions beyond adaptive immune regulation to include modulation of innate immune responses within atherosclerotic lesions.