Abstract 13609: Heterogeneous Populations of Cytotoxic CD4 T Cells Are Expanded in Atherosclerotic Plaques of Patients With Type 2 Diabetes

Abstract

Introduction: Atherosclerotic cardiovascular disease (ACVD) is the main cause of morbidity and mortality in patients with type 2 diabetes (T2D). ACVD is more severe and diffuse in T2D than in subjects with no diabetes (ND). Moreover, cholesterol reduction in T2D leads to less plaques resolution. While the role of macrophages in T2D plaque pathology has been investigated, no studies have systematically investigated the heterogeneity of CD4 T cells in human plaques. Hypothesis: Plaques of patients with T2D have a greater CD4 T cell heterogeneity and pathogenic phenotypes compared with plaques of ND subjects. Methods: To identify the specific T cell alterations in plaques we analyzed scRNA sequencing data of >80,000 plaque immune cells from 22 patients undergoing carotid endarterectomy with or without T2D (54.5% T2D). Results: Unbiased clustering of CD45+ cells identified a total of 24 immune cell clusters, including CD4 T cells that presented similar cell frequencies between T2D (~11%) and ND patients (~10%). CD4 T cells comprise 7 clusters: naïve, proliferating, central memory (CM), effector memory (EM), T regulatory (Tregs), cytotoxic (CTL), and gamma delta (γδ) T cells. CD4 CTLs expressed GZMB, GNLY, PRF1 , and could be divided into TRAC +EM (cluster 9) and CTLγδ T cells expressing both TRDC and TRGC2 (cluster 5). CTLγδ T cells were significantly expanded in T2D plaques (p=0.032), and expressed high levels of GZMA and transcription factors involved in T cell differentiation such as RUNX and TBX21 . These CTLγδ T cells are enriched with sets of genes involved in T-cell activation, numerous pathways of apoptosis, cytotoxicity, chemotaxis and cytokine signaling (i.e. IL1, IL2, IL9 ). Conclusions: Our data show that plaques from patients with T2D are highly enriched in unique CTL/γδ T cells and suggest that their cytotoxic potential may contribute to the increased cardiovascular risk of subjects with T2D.