Immunological Modulation in Atherosclerosis

Atherosclerosis is a lipid-driven, chronic inflammatory disorder of the arterial wall in which immune pathways play a central role. The earliest stages are marked by endothelial dysfunction and deposition of modified lipoproteins that recruit monocytes and lymphocytes. Macrophages ingest oxidised lipids to become foam cells, while proliferating T lymphocytes—particularly pro-inflammatory CD4+ T helper 1 (Th1) cells—secrete interferon-γ and other cytokines that exacerbate lesion progression. Counterbalancing this response are regulatory T cells (Tregs) and anti-inflammatory cytokines such as interleukin-10, which can stabilise plaques and promote efferocytosis. Recent advances in immunology and biotechnology have enabled targeted modulation of these cell types, including small-molecule inhibitors of antigen-presenting cell activation, peptide-based vaccines that shift T cell phenotypes and strategies to enhance Treg function. By altering the balance between pro-atherogenic and atheroprotective immune responses, these approaches offer the prospect of reducing plaque burden, promoting plaque stability and attenuating residual inflammatory risk beyond standard lipid-lowering therapy. The global significance of such interventions lies in their potential to complement existing regimens and to address the estimated 40–50 percent of cardiovascular events attributed to persistent arterial inflammation.

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Studies in murine models have highlighted the role of proteases in T cell-mediated atherogenesis. In genetic models deficient in legumain, researchers observed reduced accumulation of CD4+ T cells in plaques and a marked decrease in lesion size, linked to impaired T cell receptor signalling, downregulation of Bcl-2 and lower secretion of interleukin-2 and interferon-γ. These findings underscore the therapeutic potential of targeting proteolytic pathways to modulate adaptive immunity. Vaccine-based strategies have also made significant strides: administration of a collagen-derived peptide induced an immune shift characterised by suppressed Th1 differentiation, expansion of Tregs and increased Ly6C^low monocytes, with concurrent reductions in plaque area and serum low-density lipoprotein cholesterol. Complementary work has investigated the central role of Th1 cells in human and experimental atherosclerosis, outlining how inhibition of Th1-associated cytokines or blockade of the transcription factor T-bet can attenuate inflammatory signalling in the arterial wall. Collectively, these diverse approaches illustrate the promise of antigen-specific immunomodulation—either through inhibition of pro-atherogenic pathways or through active immunisation—to achieve stable and lasting control of arterial inflammation.

Immunological Modulation in Atherosclerosis publication trend

The graph below shows the total number of articles in immunological modulation in atherosclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Atherosclerosis: Chronic inflammatory disease characterised by the formation of lipid-rich plaques in arterial walls.

CD4+ T cell: Subset of lymphocytes that orchestrates adaptive immune responses, including Th1 and Treg lineages.

Th1 cell: CD4+ T helper cell subtype that secretes interferon-γ and drives pro-inflammatory responses in lesions.

Regulatory T cell (Treg): CD4+ T cell subtype that suppresses inflammation and promotes plaque stability through anti-inflammatory cytokines.

Cytokine: Signalling protein released by immune cells to coordinate inflammatory and immunomodulatory responses.

T cell receptor (TCR) signalling: Intracellular cascade initiated by antigen recognition on T cells, critical for their activation and differentiation.

References

1. Legumain deficiency halts atherogenesis by modulating T cell receptor signaling. Aging Cell (2024).
2. The emerging role of Th1 cells in atherosclerosis and its implications for therapy. Frontiers in Immunology (2023).
3. COL6A6 Peptide Vaccine Alleviates Atherosclerosis through Inducing Immune Response and Regulating Lipid Metabolism in Apoe−/− Mice. Cells (2024).
4. Immunomodulation Therapies for Atherosclerosis: The Past, the Present, and the Future. International Journal of Molecular Sciences (2023).