A Novel Role for Triglyceride Metabolism in Foxp3 Expression.

Howie D., Ten Bokum A., Cobbold SP., Yu Z., Kessler BM., Waldmann H.

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.

DOI

10.3389/fimmu.2019.01860

Type

Journal article

Publication Date

2019-01-01T00:00:00+00:00

Volume

10

Keywords

differentiation, lipotoxicity, metabolism, metabolomics, regulatory T (Treg) cell, tolerance, Animals, CD2 Antigens, CD52 Antigen, Cell Line, Diacylglycerol O-Acyltransferase, Fatty Acids, Female, Forkhead Transcription Factors, Humans, Lipid Droplets, Metabolome, Mice, Protein Kinase C, T-Lymphocytes, Regulatory, Triglycerides

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