TCDD aggravates the formation of the atherosclerotic plaque in ApoE KO mice with a sexual dimorphic pattern.

Aryl hydrocarbon receptor (AhR) ligands are recognized as aggravating factors in cardiovascular diseases but little is known about the role of the AhR in atherosclerosis considering the effects of age and gender. We exposed male and female ApoE knock-out mice, a model to study the pathogenesis of atherosclerosis, to a potent AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by an intraperitoneal injection of 1 µg/kg/week for 8 weeks. Atherosclerotic lesions, histological parameters and critical atherosclerotic markers in aorta were analysed. TCDD increased atherogenic lesions in 35-week old female mice, leading to a switch of vascular smooth muscle cells (VSMCs) from a contractile to a pro-atherogenic phenotype and increased expression for VCAM1. AhR activation accelerates the formation of atherosclerotic plaques with sex and age differences due to the phenotypical switch of VSMCs.

Control of the T follicular helper-germinal center B-cell axis by CD8⁺ regulatory T cells limits atherosclerosis and tertiary lymphoid organ development.

BACKGROUND: The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. METHODS AND RESULTS: Here, we analyzed the contribution of Qa-1-restricted CD8(+) regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8(+) regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. CONCLUSIONS: This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenic and that CD8(+) regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach.