Mucosal-Associated Invariant T Cells Promote Atherosclerosis Through Monocyte-Driven Inflammation

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes that may contribute to inflammatory responses, although their specific role in atherosclerosis remains poorly understood. In this study, we identified MAIT cells within human atherosclerotic plaques and found that they were significantly enriched among CD3 T cells in plaques compared to matched peripheral blood samples. MAIT cells within plaques exhibited an activated phenotype and showed upregulation of genes associated with inflammation and cellular activation, compared to circulating MAIT cells from the same patients. Using murine models, we found that low-density lipoprotein receptor (Ldlr)-/- mice carrying the CAST locus, which confers naturally higher frequencies of MAIT cells, displayed increased MAIT cell accumulation in both the liver and atherosclerotic plaques when fed a high-cholesterol diet. In contrast, MAIT cell-deficient Ldlr-/-CAST MR1-/- mice exhibited a reduced atherosclerotic burden, diminished liver fibrosis, smaller myocardial infarcts following coronary artery ligation, without significant changes in plasma cholesterol levels. These atheroprotective effects were accompanied by lower monocyte counts in the bone marrow and blood, as well as reduced plaque macrophage accumulation in the plaques. Furthermore, deletion of CCR2, which impairs monocyte mobilization, abrogated the pro-atherogenic effects of MAIT cells, indicating that MAIT-driven atherogenesis occurs through a monocyte-dependent mechanism. Taken together, these findings identify MAIT cells as active contributors to vascular inflammation and position them as potential therapeutic targets for atherosclerosis and its complications.