Thursday, April 3, 2025
4/3/2025
Role of apoE in HDL-mediated enhanced survival of human regulatory T-cells - Abstract Regulatory T cells (Tregs) mediate anti-inflammatory functions and have been most associated with self- immunity and autoimmune diseases. However, given the underlying role of subclinical or persistent low-level inflammation in metabolic and cardiovascular diseases, attention has recently focused on the potential role of Tregs in controlling the proinflammatory milieu in these pathologies. A subset of Tregs, the effector memory Tregs, are the most suppressive, but are also the most transient. We made the striking observation that high- density lipoproteins (HDL), but not other lipoproteins, significantly improved Treg survival. These findings offer an explanation for the positive correlation we found between HDL cholesterol and Treg abundance. Our preliminary data show that HDL preferentially bind and are internalized by Treg memory subsets, particularly by effector memory Tregs, promoting their survival by reducing effector caspase activation. Mechanistically, our new data also suggest that this HDL pro-survival effect may occur via activation of the AKT signaling pathway, which results in enhanced de novo fatty acid synthesis and reduced mitochondrial oxidative stress. Since HDL is a family of related particles with complex mixtures of lipids and proteins, we started exploring which HDL subspecies or components stimulate Treg survival. We found that the pro-survival effect was mediated by the HDL protein component, and particularly the relatively minor HDL protein constituent, apolipoprotein (APO)E, and/or other proteins that co-reside on APOE-containing HDL. In contrast, the major HDL scaffold proteins from the APOA family did not play a major role. Our overarching hypothesis is that APOE-rich HDL specifically interact with Tregs to trigger pathways that limit caspase-dependent apoptosis. Aim 1 will identify the intracellular signaling pathways involved in HDL-mediated survival of Treg, notably the receptor(s) involved in HDL binding/ internalization by memory Tregs and the mechanisms by which HDL promote Treg survival. We will also determine the effect of HDL on Treg suppression. Aim 2 will identify specific HDL subspecies and protein components that promote Treg survival. We will also perform deletional and site-directed mutagenesis experiments to identify the critical region(s) of APOE, to inform explorations of synthetic peptides that can mimic APOE’s pro-survival effects on memory Tregs. Aim 3 will assess the involvement of APOE-rich HDL in Treg survival in vivo. We will leverage the Cincinnati Pediatric Diabetes and Obesity Center cohort and probe the association between absolute numbers of Treg subsets, their functional characteristics, and HDL subspecies, before and after weight reduction surgery. The ability of HDL subspecies collected before and after surgery to promote memory and effector memory Treg survival will be studied. By identifying specific cellular pathways and specific lipoprotein species responsible for the Treg survival effects, we will open new avenues for potential therapeutic intervention aimed at modulating Treg function in a host of auto-immune and chronic metabolic diseases.
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