Abstract 12926: Senescent CD8 T Cells are Enriched in Atherosclerotic Plaques From Patients With Type 2 Diabetes and Their Circulating Levels Are Normalized by Intensive Lipid Lowering

Abstract

Introduction: Senescence is a key driver of age-related chronic inflammatory diseases including type 2 diabetes (T2D). Senescent T cells lose their ability to control tissue homeostasis and present aberrant cytokine and cytotoxic responses that ultimately cause tissue damage. Atherosclerotic plaques from T2D present more severe pathology than patients with no diabetes (ND) and circulating senescent CD8 T cells are increased in T2D and associated with myocardial infarction. However, whether senescent CD8 T cells accumulate in atherosclerotic plaques of T2D patients is unknown. Hypothesis: Senescent T cells infiltrate atherosclerotic plaques and contribute to the aggravated cardiovascular risk in T2D. Methods: We performed unbiased scRNA-seq analysis (75,049 total cells) of plaques from T2D (n=12) and ND patients (n=10) enrolled in the Athero-In Study. Circulating immune cells from T2D (n=16) and ND (n=6) patients enrolled in the CHORD study were analyzed using mass cytometry (CyTOF) before and after lipid lowering treatment. Results: We found a cluster of CD8 T cells expressing a senescence gene signature ( B3GAT1, KLRG1, KLRF1), as well as proinflammatory ( IFNG, TNF, CCL4, CCL5 ) and cytotoxic ( GZMB, PRF1, GNLY ) genes. Plaque senescent CD8 T cells showed a terminally differentiated effector memory phenotype (TEMRA) with high expression of CX3CR1 and low expression of lymphoid-homing genes ( SELL, CCR7) . CyTOF analysis revealed that circulating senescent CD8+ CD28- CD57+ T cells were increased in T2D compared to ND patients. Treatment with PCSK9 inhibitor plus statin/ezetimibe, which reduced LDL levels by >70% at 4 weeks, normalized senescent CD8 T cell frequency in T2D patients to the levels of ND subjects at baseline. No changes were observed in cells from cholesterol-reduced ND patients. Conclusions: Our results show that senescent CD8+ T cells are enriched in atherosclerotic plaques and blood of T2D patients. The observation that acute lipid lowering normalized circulating senescent CD8 T cells in T2D patients indicates that T cell senescence can be improved by more aggressive lipid control in high risk T2D subjects. Further analyses are needed to understand how T cell senescence contributes to atherosclerosis and impaired regression in T2D.