Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

Abstract

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4 + Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ-or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4+ and γδ + T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.

T lymphocyte regulation by mevalonate metabolism

“…In addition, oxysterols have been identified as agonist ligands of the retinoic acid receptor-related orphan receptors a and gt (RORa and RORgt), which are members of the nuclear hormone receptor superfamily (24). Oxysterols are RORgt agonists and serve as potential endogenous RORgt ligands in promoting the differentiation of mouse and human CD4 + T helper 17 (T H 17) cells (25). Thus, LXRb acts as a sensor of intracellular sterol content and may couple sterol metabolism to innate and adaptive immune responses.…”

Adipose-Derived Mesenchymal Stem Cells Ameliorate Ulcerative Colitis Through miR-1236 Negatively Regulating the Expression of Retinoid-Related Orphan Receptor Gamma

“…Retinoid-related orphan receptor g (RORg) is an orphan nuclear receptor and expresses in several immune cell types, including CD4 + Th17 cells (Soroosh et al, 2014). Due to its essential role in driving IL-17 production, RORg represents a potential target for therapeutic intervention, and a number of antagonists that inhibited Th17 cell differentiation have been published (Huh et al, 2011).…”

Impact of environmental factors on alloimmunity and transplant fate

“…In a murine model of islet Cholesterol also plays a role in T cell polarization following activation. While oxysterol-induced LXR prevented Th17 generation by inhibiting aryl hydrocarbon receptor-dependent (AHR-dependent) IL-17 transcription (60), non-LXR agonist oxysterols induced RORγt, the master transcriptional element controlling Th17 development (61). Adding oxysterols to naive T cells under polarizing conditions promoted the development of Th17 cells (61).…”