CD27+ γδ T Cells Drive Plaque Instability in Advanced Atherosclerosis: Targeting CXCR3 for Therapeutic Intervention

Abstract

BackgroundAtherosclerosis is a chronic inflammatory disease of the arterial wall that underlies most myocardial Ischaemic events. While multiple immune subsets contribute to plaque progression and instability, the role of {gamma}{delta} T cells remains poorly understood. We examined the contribution of {gamma}{delta} T cells to lesion development, progression and instability, and explored the therapeutic potential of their pharmacological blockade. MethodsTo investigate the role of {gamma}{delta} T cells, chimeric atherosclerosis-prone mice lacking {gamma}{delta} T cells were utilized in both loss- and gain-of-function experiments. Mixed bone marrow chimeras were generated to assess the role of {gamma}{delta} T cell-derived interferon-{gamma} (IFN-{gamma}) and perforin (Pfp). The therapeutic efficacy of AMG487 on plaque stability was evaluated in a preclinical tandem-stenosis mouse model. Lesion size, plaque composition, and stability were assessed using histology, immunoassays, and molecular biology techniques. ResultsCD27+ {gamma}{delta} T cells accumulated in atherosclerotic lesions and promoted plaque progression and instability via IFN-{gamma}- and Pfp-dependent manners. As early infiltrators, they amplified necrosis and inflammation by enhancing immune cell recruitment, thereby exacerbating lesion vulnerability. CXCR3 antagonism with AMG487 inhibited {gamma}{delta} T cell recruitment to plaques, reduced lesion size, and promoted features of plaque stability, including increased smooth muscle cell content and thicker fibrous caps. ConclusionsCD27 {gamma}{delta} T cells, which promote inflammation and necrosis through both direct and indirect mechanisms, are key drivers of plaque progression and instability. Targeting their recruitment via CXCR3 blockade enhances plaque stability and may represent a promising therapeutic strategy to reduce the risk of myocardial infarction.