Immunometabolism and the Cardio-Renal Axis in T1D-associated Atherosclerosis: Insights from the CaRe T1D Biobank

Abstract Cardiovascular disease (CVD) caused by atherosclerosis remains the leading cause of mortality in individuals with type 1 diabetes (T1D). Although T cells are well known to play a critical role in T1D development, attacking and destroying the insulin-producing β-cells, very little is known about the expansion of specific T cell populations and clones in cardiovascular complications associated with T1D. Our project aims to dissect the relationship between increased recruitment and expansion of harmful T cells in the atherosclerotic milieu of T1D, leveraging the unique resources of the CaRe-T1D biobank. By employing single cell-T cell receptor- sequencing (scTCR-seq) and cellular indexing of transcriptomes and epitopes-sequencing (CITE-seq) of circulating PBMCs, we will illuminate T cell populations altered in T1D and investigate their adhesion to human coronary artery endothelial cells. By performing TCR-seq on atherosclerotic lesions and elucidate localization of T cell population associated with lesion stage by spatial and global proteomics we will delineate the role these T cells might play in the increased CVD risk associated with T1D. We hypothesize that atherosclerotic lesions in T1D are characterized by increased accumulation of specific T cell populations and clones correlating with lesion severity and necrosis, and that the accumulation of T cells in T1D-related atherosclerotic and renal kidney lesions mirror each other, driven by similar immunometabolic perturbations. Two specific aims will address this hypothesis. We will 1) Clarify mechanisms of increased T cell adhesion and tissue recruitment in T1D cases; and 2) Investigate clonal expansion of CD4+ and CD8+ T cells in atherosclerotic lesions in T1D. By correlating selective T cell markers with a thorough characterization of lesion features, our studies will provide novel information on T cells in the pathogenesis of atherosclerosis and renal kidney injury in T1D in contrast with controls and T2D. Our project is led by a coalition of scientists and physician-scientists with extensive expertise in diabetes, diabetes complications (atherosclerosis and diabetic kidney disease) and immunology, with deep methodological proficiency in human studies, multi-omics analyses, and integrated biology. This diverse expertise ensures a holistic approach and full utilization of the unique resources of the CaRe-T1D, enabling us to navigate the complex interplay of metabolic and immune processes in T1D with unparalleled depth and precision. Our comparative analyses between peripheral blood mononuclear cells, atherosclerotic lesions and kidneys from the CaRe-T1D biobank will provide a robust platform for identifying and testing potential therapeutic targets. Our focus on the metabolic-immune interface within atherosclerotic lesions, and specifically on identifying specific T cell populations and clones, offers a novel perspective on pathogenesis, positioning our study to make significant contributions to the field.