Empowering regulatory T cells to restore immune tolerance and reduce inflammation-driven atherosclerosis

Comment on: Roy, P., Bellapu, A., Suthahar, S.S.A. et al. Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease. Nat Cardiovasc Res 4, 841–856 (2025). https://doi.org/10.1038/s44161-025-00671-9 Atherosclerotic cardiovascular disease (ASCVD) is a well-established lipid-driven inflammatory disease where both lipid-lowering and anti-inflammatory pharmacological interventions can reduce disease burden. Lipid-lowering treatment has been used in clinical practise for decades; however, the first anti-inflammatory drug approved for cardiovascular indications (low-dose colchicine) was only introduced in 2023, suggesting an underappreciation of the inflammatory cascade in ASCVD. Indeed, chronic activation of the immune system in atherosclerosis was first observed in the late 1800s by the pathologist Rudolf Virchow, a finding that was reinforced by Russell Ross in the 20th century. However, thanks to cutting-edge sequencing techniques, we are now starting to understand the origin and nature of vascular inflammation, by identifying specific immune subsets and their physical location within the atherosclerotic plaque.1 This technological advancement has improved our understanding of the heterogeneous cellular landscape of human plaques and our appreciation of the role that adaptive immunity plays in propagating the chronic inflammation associated with atherosclerosis. Particularly, T lymphocytes, key cellular effectors of the adaptive immune response, are common in advanced atherosclerotic lesions and show an activated phenotype, suggesting these T cells may have become reactive against self-antigens.2 Although mechanisms of central and peripheral central tolerance normally prevent the induction of autoreactive T cells, this mechanism can be compromised as observed in autoimmune disease such as multiple sclerosis, rheumatoid, and psoriatic arthritis, where autoreactive T cells cause tissue inflammation. Whether such a break of tolerance is also happening in ASCVD or whether T-cell activation simply represents a bystander of atherosclerosis-driven inflammation has intrigued the field for a long time. The identification of autoreactive T cells, mostly of the CD4+ subsets, against self-antigens, including ApoB100 residues and the recognition that T cells in the plaque are clonally expanded, suggest that T cells can undergo activation similar to autoimmune diseases,3 although this does not answer the question of causality.