The impact of diet-dependent metabolic reprogramming on phenotype switching of ApoB-reactive T cells in atherogenesis

• Applicant: Dr. Felix Nettersheim
• Subject Area: Cardiology, Angiology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466180651

Atherosclerosis is a chronic inflammatory disease that involves an adaptive immune response against plaque-associated autoantigens. Particularly, Apolipoprotein B-specific CD4+ T cells (ApoB+ T cells) have been identified as critical disease modulators. The host group has established a novel technique to directly label ApoB+ T cells by tetramers that enable detection and analysis of these cells. Additionally, the group demonstrated that preventive immunization of atherosclerosis-prone mice with ApoB peptides induces expansion of ApoB+- regulatory T cells (Tregs) and confers atheroprotection. Yet, more recent work revealed that ApoB+ Tregs can lose their atheroprotective capacities during atherogenesis and acquire a proatherogenic phenotype. This phenotype switching is accelerated by western diet. The underlying mechanisms are largely unknown, although clarification of these is key for realizing an ApoB-based vaccination against atherosclerosis: Immunization-induced expansion of ApoB+-Tregs will facilitate long-term atheroprotection only if expanded Tregs do not subsequently convert into proatherogenic subtypes. Recent evidence suggests that metabolic reprogramming toward a glycolytic metabolism is critical for differentiation and functionality of effector T cells while destabilizing Tregs. The applicant proposes to investigate whether proglycolytic metabolic reprogramming is involved in phenotype switching of ApoB+ T cells in atherogenesis and whether such reprogramming is influenced by diet. Transgenic mouse models as well as adoptive cell transfer experiments will be utilized to assess if cell-specific inhibition of glycolytic metabolism affects formation of proatherogenic ApoB+ effector T cells and stability of ApoB+ Tregs. Phenotypes and metabolic properties of ApoB+ T cells will be characterized by flow cytometry, RNA-sequencing, and in vitro assays. Additionally, the impact of diet on phenotype switching of ApoB+ T cells in healthy humans and patients with subclinical atherosclerosis will be analysed. Here, peripheral blood mononuclear cells from participants of a large clinical study will be subjected to combined single-cell transcriptome and cell surface phenotype analysis. In summary, the proposed project will help to understand how metabolic reprogramming and diet influence the conversion from immune tolerance to proatherogenic immunity and, potentially, form the basis for development of novel treatment strategies targeting such switching.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Klaus Ley