Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists

Desmosterol acts as an endogenous RORγ agonist during differentiation of CD4 + T cells into the T H 17 lineage, where there is increased cholesterol biosynthesis and uptake and decreased cholesterol metabolism and efflux that cause accumulation of desmosterol. Retinoic acid receptor–related orphan receptor γ (RORγt) controls the differentiation of naive CD4 + T cells into the T H 17 lineage, which are critical cells in the pathogenesis of autoimmune diseases. Here we report that during T H 17 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 T H 17 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 T H 17-inhibiting sterol receptor LXR. Thus, T H 17 differentiation is orchestrated by coordinated sterol synthesis, mobilization and metabolism to selectively activate RORγ.