Immune mechanisms hindering plaque regression in type 2 diabetes

About This Grant

SUMMARY Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in Type 2 diabetes (T2D) patients. Despite standard-of-care treatments aimed at reducing cardiovascular (CV) risk in T2D patients, outcomes remain suboptimal, with persistently high CV event rates observed even in well-managed T2D patients. T2D is projected to affect >600 million people worldwide in the next two decades. A deeper understanding of the underlying mechanisms to prevent and cure ASCVD in T2D is urgently needed. In preliminary work, using single cell technologies and unbiased computational methods to study human carotid plaques and coronaries, we discovered an expansion of effector and highly cytotoxic γδ T cells in T2D plaques, with higher frequencies in males. Notably, these γδ T cells were also expanded in the blood of T2D individuals. Aggressive lipid lowering interventions in a clinical trial reduced their circulating levels, but exclusively in T2D females. These findings suggest that γδ T cells contribute to aggravated atherosclerosis in T2D. Additionally, the transcription factor ZEB2, a GWAS candidate gene associated with T2D, CAD and MI, has been identified as a candidate driver of the effector and cytotoxic functions of γδ T cells. Utilizing a mouse model of T2D and atherosclerosis, we observed that T2D impedes plaque regression despite lipid-lowering interventions. We identified a significant increase in γδ T cells within atherosclerotic plaques of mice with T2D, consistent with observations of increased γδ T cells in human T2D plaques. This suggests that expanded γδ T cells in T2D plaques directly contribute to exacerbated atherosclerosis progression and may hinder plaque regression. Based on these compelling preliminary findings, we propose two independent aims: Aim 1 will investigate the contribution of γδ T cells to atherosclerosis progression in T2D, including the role of ZEB2 in their function, while Aim 2 will focus on identifying the contribution to impaired plaque regression in T2D, along with the role of ZEB2 in these processes. These studies aim to address critical gaps in understanding the effects of T2D on plaque inflammation and atherosclerosis and elucidate the molecular basis for aggravated atherosclerosis, impaired plaque regression, and increased CV risk in patients with T2D. The insights gained from these investigations, which will be collected and deposited in public repositories for dissemination, will guiding the development of precise therapies aimed at reducing CV risk in patients with T2D.