Project Details
Projekt
Characterization of immune determinants of aggravated atherosclerosis in patients with T2DM, obesity, and optimal LDL-C reduction
Applicant
Hauke Horstmann
Subject Area
Cardiology, Angiology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 537103624
The proposed research is based on comprehensive single-cell transcriptome analyses that have identified γδ T cells and ZEB2+ CD8+ T cells as key drivers of disease progression in T2D-associated atherosclerosis. The significance of this work lies in uncovering novel immunological mechanisms that contribute to plaque inflammation and instability, potentially enabling targeted immunomodulatory therapies. Progress from the previous grant application: • Preliminary Work 1: Development of the most comprehensive scRNAseq atlas of human atherosclerotic plaques (103,505 leukocytes from 26 patients). The analysis revealed that CD4+ and CD8+ T cells exhibit the most pronounced transcriptional changes in T2D and are associated with severe plaque phenotypes and increased cardiovascular risk. • Preliminary Work 2: Identification of GZMB+ γδ T cells, which are significantly expanded in T2D plaques and associated with fibrocalcified lesions. Their pro-inflammatory and cytotoxic transcriptional profile suggests a central role in worsening plaque pathology. Additionally, sex-specific differences in their function were observed. • Preliminary Work 3: Discovery that ZEB2+ CD8+ T cells accumulate in T2D plaques and display a senescent, cytotoxic phenotype. Network analyses confirmed ZEB2 as a central regulator of CD8+ T cell differentiation towards a pro-atherogenic and inflammatory state. • Preliminary Work 4: Integration of scRNAseq data from blood samples of CAD and T2D patients demonstrated that ZEB2+ CD8+ T cells are also overrepresented in the blood of T2D patients and persist despite intensive lipid-lowering therapy. Furthermore, activated γδ T cells were identified as strong predictors of cardiovascular mortality, laying the foundation for future biomarker-based risk stratifications. Aims: • Aim 1 investigates the mechanistic role of pro-inflammatory and cytotoxic γδ T cells in promoting plaque progression in T2D. A novel mouse model allows their targeted depletion, complemented by spatial sequencing and Imaging Mass Cytometry of human atherosclerotic plaques. • Aim 2 analyzes the role of ZEB2 in CD8+ T cells, which exhibit a senescent and cytotoxic phenotype in T2D plaques. Using a ZEB2-knockout mouse model and CRISPR-mediated modulation of human CD8+ T cells, the study aims to determine whether blocking ZEB2 can reduce inflammatory risk in T2D-associated atherosclerosis. These independent studies will provide a mechanistic understanding of T cell-mediated inflammatory processes in atherosclerosis and open translational avenues for novel immunomodulatory therapies in patients with T2D and cardiovascular disease.
DFG Programme
WBP Fellowship
International Connection
USA
