Abstract Body (Do not enter title and authors here): Immune checkpoints are a group of immune regulatory plasma membrane proteins expressed on antigen-presenting cells and T cells, which are crucial for maintaining self-immune tolerance and modulating the effectiveness of T cell immune responses. The importance of selected immune checkpoints in cardiovascular diseases have been widely recognized. However, we identified a significant knowledge gap in the comprehensive understanding of immune checkpoint signaling across multiple levels in cardiovascular diseases. To bridge this gap, we developed a framework that encompasses disease stages and cell types regulated by immune checkpoint axes within the contexts of three major aortic diseases such as abdominal aortic aneurysm, atherosclerosis, and diabetic aortic pathology. Initially, at the transcriptional level, we analyzed the expressions of 58 pairs of immune checkpoint genes in mouse aorta across three models of abdominal aortic aneurysm, four models of hyperlipidemia and atherosclerosis, and three models of diabetes, each representing various stages of the respective diseases. At the single-cell level, we investigated the gene enrichment within separate clusters of aortic cells under diseased conditions. From the results, we found that among the immunosuppressive or double functional immune checkpoints, CD155 expression patterns were different from that of CD274 in more than 50% samples, suggesting that CD155 may play immunosuppressive/anti-inflammatory roles in aortic diseases that are different from CD274. Therefore, we performed flow cytometry to investigate potential regulation of the TIGIT/CD155 axis at the cellular levels in four organs of ApoE-/- mice compared to wild type. The results identified that TIGIT/CD155 axis is upregulated in aortic CD45+ leukocytes but not in CD45- non-leukocyte cellular compartments. CD155 enrichments were identified in CD45+CD11b+CD11c+ cells in blood and kidney, as well as in CD45+CD11b-CD11c+ cells in the lung. Furthermore, among the three functional markers used to identify the subclusters of heterogeneous aortic antigen-presenting cells—CD206, CX3CR1, and CD103—positive correlations were observed between CD155 expressions and the anti-inflammatory marker CD206, while correlations with CX3CR1 and CD103 were absent. These results have demonstrated that CD155-CD206 pathway may play surrogative roles to CD274 in suppressing inflammation and immune responses in atherosclerosis and aortic diseases.