Sterols are needed in proliferating cells as components of cell membranes and as signalling molecules for nuclear and cell-surface receptors, and their levels are controlled by a balance of synthesis, uptake, metabolism and efflux. Consistent with this requirement for sterols in activated T cells, Hu et al. show that the expression of most genes involved in cholesterol biosynthesis and uptake is increased, whereas the expression of genes involved in cholesterol metabolism (especially oxysterol formation) and efflux is decreased, in activated T cells cultured under TH17 cell-polarizing conditions, as well as during the in vitro differentiation of TH1 cells and regulatory T (TReg) cells. Moreover, the use of inhibitors (such as ketoconazole) that block an enzyme involved in cholesterol synthesis selectively decreased TH17 cell differentiation without affecting the expression of RORγ.
As blocking of cholesterol synthesis selectively decreased the transcription of RORγ target genes, the authors next investigated whether cholesterol precursors could function as ligands for RORγ. Among those tested, desmosterol and zymosterol potently increased co-activator recruitment by RORγ and were able to outcompete binding by RORγ antagonists. Desmosterol and zymosterol also promoted RORγ transcriptional activity in a reporter assay. Finally, the addition of these sterols to TH17 cell-polarizing cultures overcame the effects of cholesterol synthesis blockade by ketoconazole, and increased IL-17 production and TH17 cell differentiation in an RORγ-dependent manner. Notably, desmosterol did not increase the differentiation of TH1 cells or TReg cells.
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