Mucosal-associated invariant T cells promote atherosclerosis through monocyte-driven inflammation

Abstract Aims Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes involved in antimicrobial defence and inflammatory regulation, yet their contribution to atherosclerosis remains poorly defined. This study aimed to characterize the distribution, phenotype, and functional role of MAIT cells in human atherosclerotic lesions and complementary murine models. Methods and Results MAIT cells were identified using MHC class I-related protein 1 (MR1) tetramers loaded with the agonist 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU). They were significantly enriched among CD3+ T cells in human carotid atherosclerotic plaques compared with matched peripheral blood. Plaque-resident MAIT cells displayed an activated, exhaustion-prone phenotype and a distinct transcriptional profile characterized by upregulation of inflammatory, stress-response, and chemotactic pathways, as revealed by bulk RNA sequencing of purified cells. In murine models, low-density lipoprotein receptor-deficient (Ldlr−/−) mice carrying the CAST locus, which confers increased MAIT cell frequency, exhibited enhanced MAIT cell accumulation in the liver and aorta under a high-cholesterol diet. We identified mature MAIT in the bone marrow which displayed activated state. Moreover, Bulk RNA sequencing of bone marrow-sorted MAIT cells from these mice revealed transcriptional signatures consistent with immune activation and enhanced myelopoiesis. In contrast, MAIT cell-deficient Ldlr−/−CAST MR1−/− mice showed reduced atherosclerotic burden, decreased liver fibrosis, and smaller myocardial infarcts following coronary artery ligation, without changes in plasma cholesterol levels. These protective effects were associated with reduced myeloid progenitors and bone marrow and circulating monocytes, as well as decreased macrophage accumulation within plaques. Importantly, disruption of monocyte mobilization via CCR2 deficiency abrogated MAIT cell–dependent effects, demonstrating a monocyte-mediated mechanism. Conclusions MAIT cells accumulate in human atherosclerotic plaques and acquire a pro-inflammatory, functionally altered phenotype. Experimental evidence demonstrates that MAIT cells promote atherosclerosis and its complications by enhancing myelopoiesis and monocyte-driven vascular inflammation. These findings identify MAIT cells as previously unrecognized regulators of monocytosis and highlight their potential as therapeutic targets in atherosclerotic cardiovascular disease.