Unravelling Treg Plasticity in Atherosclerosis

• Applicant: Professor Dr. Holger Winkels
• Subject Area: Cardiology, Angiology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398146742

Regulatory T cells (Tregs) play an important role as anti-inflammatory modulators of atherosclerosis. Mouse models of atherosclerosis demonstrate the vanishing of these cells from atherosclerotic lesions in disease progression. This is in line with several reports describing a reduction in circulating Tregs of patients suffering from acute coronary syndrome. Interestingly, recent work of the host institution and others demonstrated loss of the suppressive phenotype of Tregs and their conversion into a pathogenic, T helper cell-like phenotype in atherosclerosis. However, the underlying mechanisms of this phenomenon are not well understood. Furthermore, until recently, technology was missing allowing to monitor antigen-specific CD4+ T cells and particularly Tregs in atherosclerosis. The host institution specifically designed a tool which allows for the detection of Tregs recognizing peptides of ApolipoproteinB-100 (ApoB100), a major component of low-density lipoprotein and proposed auto-antigen in atherosclerosis. The applicant proposes several experimental strategies and identifies scientific aims based on the recent finding at the host institution. First, the applicant will determine at which point in time in atherosclerosis the conversion of ApoB100-specific Tregs occurs by applying a new Treg fate mapping mouse model. Furthermore, the transcription factor and cytokine profile of ApoB100-specific current Tregs and exTregs cells will be assessed. T cell receptor sequencing will help to identify the clonality of ApoB100-specific exTregs and whether former Tregs stem from current Tregs. This will further point to whether all ApoB100-specific Tregs have the potential to switch or only certain clones. Single cell RNA sequencing and ATAC sequencing will help to identify subpopulations of ApoB100-specific Tregs and exTregs and genomic active regions. This will potentially lead to the discovery of transcription factors that are responsible for the conversion and new therapeutic targets to prevent Treg conversion. Furthermore, the contribution of ApoB100-specific exTregs to atherosclerosis will be determined by adoptive cell transfers. The host institution recently demonstrated atheroprotection of atherosclerotic mice by vaccination with ApoB100 peptides. This was accompanied by an expansion of Tregs. Thus, the applicant will determine whether this vaccination strategy prevents the conversion of Tregs in atherosclerosis. This proposal will contribute to a better understanding of Treg biology in atherosclerosis. These insights will help to determine potential therapeutic targets aiming to stabilize the Treg population in the progression of atherosclerosis. Several bail-out strategies are proposed within the applicant’s grant application and all techniques, mouse strains and double knock-out mice are available at the host institution.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Klaus Ley