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. 2025 Jul;4(7):841-856.
doi: 10.1038/s44161-025-00671-9. Epub 2025 Jun 18.

Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease

Payel Roy  1   2   3 , Anusha Bellapu  4 , Sujit Silas Armstrong Suthahar  5 , Mohammad Oliaeimotlagh  4 , Qingkang Lyu  4 , Smriti Parashar  4 , Jeffrey Makings  5 , Runpei Wu  5 , Sunil Kumar  4 , Megh Mehta  4 , Austin W T Chiang  6 , Alessandro Sette  7   8 , Coleen A McNamara  9   10 , Klaus Ley  11   12
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Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease

Payel Roy et al. Nat Cardiovasc Res. 2025 Jul.

Abstract

Atherosclerosis underlies most coronary artery disease (CAD). It involves a significant autoimmune component against apolipoprotein B (APOB). In this study, we used short activation-induced marker (AIM) assays to characterize APOB-reactive CD4+ T cells in patients with angiographically verified CAD. APOB-reactive CD4+ T cells expressing CD25 and 4-1BB markers were the most abundant. Their frequency correlated positively with CAD severity. Transcriptomic analysis revealed that these cells were clonally expanded and significantly enriched in genes expressed in tissue-homing effector regulatory T (eTreg) cells. They shared signatures with CD4+ T cells in mouse and human plaques, including expression of the plaque-homing chemokine receptor CXCR6. With increasing disease severity, the Treg signature was progressively and significantly lost. Conversely, APOB-specific Treg cells from patients with severe CAD gained glycolytic and interferon response signatures. We conclude that mild CAD is associated with a regulatory program in APOB-reactive CD4+ T cells, which is replaced by a pro-inflammatory program in patients with severe CAD.

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Conflict of interest statement

Competing interests: K.L. is the founder and co-owner of Atherovax, Inc. He receives no compensation from Atherovax. No Atherovax funds were used in this study. K.L. and P.R. are named as co-inventors on a patent application (provisional application no. 63/789,764, filed by the La Jolla Institute for Immunology, approval status pending) that is related to the use of human APOB epitopes and related methods in modulating inflammatory responses and treating adverse cardiovascular events, disease and atherosclerosis. The other authors declare no competing interests.

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