Abstract
Retinoic acid receptor–related orphan receptor γ (RORγt) controls the differentiation of naive CD4+ T cells into the TH17 lineage, which are critical cells in the pathogenesis of autoimmune diseases. Here we report that during TH17 differentiation, cholesterol biosynthesis and uptake programs are induced, whereas their metabolism and efflux programs are suppressed. These changes result in the accumulation of the cholesterol precursor, desmosterol, which functions as a potent endogenous RORγ agonist. Generation of cholesterol precursors is essential for TH17 differentiation as blocking cholesterol synthesis with chemical inhibitors at steps before the formation of active precursors reduces differentiation. Upon activation, metabolic changes also lead to production of specific sterol-sulfate conjugates that favor activation of RORγ over the TH17-inhibiting sterol receptor LXR. Thus, TH17 differentiation is orchestrated by coordinated sterol synthesis, mobilization and metabolism to selectively activate RORγ.
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Change history
15 July 2015
In the version of this article initially published, the zymosterol and zymostenol structures shown in Figure 3a were depicted with a double bond at C14-C15, where there should have been a single bond. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank X. Lu and D. Bousley for help on maintaining cells and mice and C. Van Huis for help on extraction with organic solvents. This work was supported in part by US National Institutes of Health grant AI-47450 to G.D.G.
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X.H. designed and conceptualized the research and wrote the manuscript. Y.W. performed ROR assays. Y.W. and X.H. conducted TH17 experiments. Y.W., L.-Y.H. and X.L. contributed to gene expression and flow cytometry analyses. J.M.W. analyzed sterol and sterol sulfate levels using LC/MS/MS. L.-Y.H., C.A.L. and B.M.S. contributed to in vivo experiments. R.W.M. established the ROR assays. T.D.A. provided structural insights. T.D.A., L.L.C., P.L.T. and G.D.G. provided constructive suggestions, helped analyze selected data and contributed to writing of the manuscript.
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All authors except J.M.W. are employees of Lycera Corp. J.M.W. is employed by Seventh Wave Laboratories.
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Hu, X., Wang, Y., Hao, LY. et al. Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists. Nat Chem Biol 11, 141–147 (2015). https://doi.org/10.1038/nchembio.1714
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DOI: https://doi.org/10.1038/nchembio.1714
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