JMA Journal

Figure 1. Classical model of atherosclerotic plaque development based on the response-to-injury hypothesis.
Endothelial injury promotes monocyte recruitment and smooth muscle cell migration into the intima, where they proliferate. Monocytes differentiate into macrophages and foam cells on the uptake of oxidized LDL. T cells infiltrate the plaque and contribute to local inflammation by secreting cytokines and interacting with antigen-presenting cells. Perivascular adipose tissue surrounding the vessel may also influence plaque development through immune and paracrine signaling.
LDL: low-density lipoprotein; SMC: smooth muscle cell.

Figure 2. Macrophages and T cells are both abundant in human atherosclerotic plaque.
(A) H&E section of an early fibroatheroma; the lipid-rich pool is labeled as LP within the intima. (B) Serial Movat Pentachrome section indicating the overall plaque architecture. (C) Immunohistochemistry against the pan-macrophage marker CD68 (brown). (D) Immunohistochemistry for the pan-T cell marker CD3 (brown). (E-H) Higher-magnification views of the larger black boxed areas in panels A-D, respectively, with labeled features indicated. (I-L) Higher-magnification views of the smaller red boxed areas in panels A-D, respectively (all located in the intima). (G, K) CD68 staining confirms that macrophages are distributed throughout the lesion but are most concentrated along the lipid-rich pool and the luminal side of the intima. (H, L) CD3 staining shows T cells dispersed throughout the plaque, with a predilection for the lipid-rich pool as well as the media and the adventitia. Scale bars: top row = 1 mm; middle row = 200 μm; bottom row = 50 μm.
A: adventitia; H&E: hematoxylin and eosin; I: intima; LP: lipid-rich pool; M: media.

Figure 3. Single-cell RNA sequencing reveals diverse immune cell populations, including macrophages and T cells, in human atherosclerotic plaque.
(A) UMAP projection generated from reanalysis of single-cell RNA-seq data from human coronary artery plaques (dataset GSE131778) ⁽¹¹⁾. For this analysis, only PTPRC (CD45)-positive leukocytes were extracted and visualized, highlighting immune cell diversity within the lesion. Macrophage clusters are the most abundant, followed by T cell clusters. (B) Dot plot showing the expression of selected marker genes (x-axis) across individual clusters (y-axis) as defined in panel A. Dot size represents the percentage of cells expressing each gene in the cluster, and color intensity reflects average expression level.

Figure 4. Single-cell and spatial transcriptomic profiling reveals immune cell heterogeneity in atherosclerotic plaques.
Single-cell and spatial transcriptomic analyses revealed that macrophages and T cells are the predominant immune cell types within atherosclerotic plaques, each comprising multiple transcriptionally distinct subsets. Macrophages include resident-like populations (expressing representative markers such as LYVE1, MRC1, and FOLR2), inflammatory subsets (IL1B, TNF, CD86), TREM2^high foamy macrophages enriched for lipid-handling genes (TREM2), and CD163⁺ macrophages that adopt an M(Hb) phenotype after hemoglobin-haptoglobin exposure (CD163). CD4⁺ T cells are classified into Th1 (TBX21, IFNG), Th17 (RORC, IL17A, IL17F), and regulatory T cells (FOXP3, IL2RA, CTLA4), whereas CD8⁺ T cells include effector memory subsets (EOMES, GZMB, PRF1) and others. These immune populations exhibit distinct spatial distributions within the plaque, suggesting region-specific immune responses that may contribute to lesion progression or stability.