Regulatory T Cell Dynamics in Atherosclerotic Disease

Atherosclerosis is driven by a chronic, lipid-driven inflammatory process within arterial walls. Central to its regulation are CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs), which maintain immune tolerance and curb excessive pro-inflammatory responses. In early lesions, Tregs accumulate in response to modified lipoproteins and secrete anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-β, promoting plaque stability. Throughout disease progression, however, the balance between Treg generation, stability and plasticity is disrupted. Factors including hypercholesterolaemia, oxidative stress and alterations in signalling thresholds can impair Treg differentiation or provoke their conversion into pro-atherogenic subsets. Conversely, strategies that enhance Treg numbers or preserve Foxp3 expression have demonstrated plaque-limiting effects in preclinical models. Understanding the cellular and molecular cues that govern Treg trafficking, survival and function within atherosclerotic plaques has become a priority for devising new immunomodulatory therapies aimed at restoring vascular homeostasis and reducing cardiovascular risk.

Research from Nature Portfolio

Recent studies have revealed that lipid homeostasis directly influences Treg identity and fate. One seminal investigation demonstrated that in the context of atherosclerosis, diminished intracellular cholesterol in Tregs—achieved by infusion of lipid-free apolipoprotein AI—prevents their conversion into T follicular helper–like cells, thereby preserving Foxp3 expression and immunosuppressive function. This work identified shifts in IL-2 receptor α and STAT5 signalling, as well as altered IL-6 receptor levels, as key mediators of Treg plasticity. Parallel research has shown that dietary hypercholesterolaemia can paradoxically augment Treg development in thymus and periphery by enhancing T cell receptor signalling strength and upregulating Foxp3 transcription. These findings underscore a dual role for cholesterol in both promoting and restraining Treg populations, dependent on local tissue context and metabolic cues.

Regulatory T Cell Dynamics in Atherosclerotic Disease publication trend

The graph below shows the total number of articles in regulatory t cell dynamics in atherosclerotic disease across all publications each year (not limited to Nature Index journals).

Technical terms

Regulatory T cell (Treg): A subset of CD4⁺ T lymphocytes that express Foxp3 and suppress excessive immune activation to maintain tolerance.

Foxp3: A transcription factor essential for Treg development, lineage stability and immunosuppressive function.

Induced Treg (iTreg): Treg cells generated in the periphery from naive CD4⁺ T cells under specific cytokine or epigenetic conditions.

Natural Treg (nTreg): Tregs that develop in the thymus and maintain immune homeostasis in peripheral tissues.

Atherogenesis: The process of plaque formation in arterial walls driven by lipid deposition, inflammation and immune cell infiltration.

Mitochondrial reactive oxygen species (mtROS): Reactive molecules generated by mitochondria that can modulate cell signalling and damage cellular components.

DNA methyltransferase 1 (Dnmt1): An enzyme responsible for maintaining DNA methylation patterns, including those that regulate Foxp3 expression.

References

1. Epigenetic modification of CD4+ T cells into Tregs by 5-azacytidine as cellular therapeutic for atherosclerosis treatment. Cell Death & Disease (2024).
2. Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms. Journal of Translational Medicine (2023).
3. A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice. Frontiers in Immunology (2023).
4. Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis. Nature Communications (2018).
5. Hypercholesterolemia Enhances T Cell Receptor Signaling and Increases the Regulatory T Cell Population. Scientific Reports (2017).