Abstract
Lipid metabolism plays a key role in many cellular processes. We show here that regulatory T cells have enhanced lipid storage within subcellular lipid droplets (LD). They also express elevated amounts of both isoforms of diacylglycerol acyl transferase (DGAT1 & 2), enzymes required for the terminal step of triacylglycerol synthesis. In regulatory T-cells (Tregs), the conversion of diacylglycerols to triacylglycerols serves two additional purposes other than lipid storage. First, we demonstrate that it protects T cells from the toxic effects of saturated long chain fatty acids. Second, we show that Triglyceride formation is essential for limiting activation of protein kinase C via free diacyl glycerol moieties. Inhibition of DGAT1 resulted in elevated active PKC and nuclear NFKB, as well as impaired Foxp3 induction in response to TGFβ. Thus, Tregs utilize a positive feedback mechanism to promote sustained expression of Foxp3 associated with control of LD formation.
Highlights
Cells of both the innate and adaptive immune system have been shown to be dependent on different aspects of lipid metabolism for their development and function [1]
We show that FoxP3+ regulatory T cells have enhanced lipid droplet numbers and contain relatively increased amounts of di- and triglycerides, fatty acids, and phospholipids compared to conventional T cell (Tconv)
Exogenous fatty acids have been shown to be directed into the triglyceride synthesis pathway for storage in lipid droplets as a protective mechanism to deal
Summary
Cells of both the innate and adaptive immune system have been shown to be dependent on different aspects of lipid metabolism for their development and function [1]. Th17 cells require endogenous fatty acid synthesis for their development as inhibition of acetyl-CoA-carboxylase, a key enzyme in FA synthesis, favors development of Treg over Th17 [4]. Innate immune cells are dependent on aspects of lipid metabolism for their differentiation. Pro-inflammatory macrophages (M1) and pro-resolution M2 macrophages have opposing requirements for fatty acid synthesis and catabolism. Factors which promote M1 macrophages induce FA synthesis [6, 7] whereas anti-inflammatory signals which favor M2 macrophages drive fatty acid oxidation [8, 9]
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