LXR-Mediated Inhibition of CD4+ T Helper Cells

Abstract

TH17 cells, which require the expression of both retinoic acid receptor-related orphan receptors α and γt (RORαand RORγt) for full differentiation and function, have been implicated as major effectors in the pathogenesis of inflammatory and autoimmune diseases. We recently demonstrated that the Liver X Receptor (LXR) agonist, T0901317 (T09), also displays high-affinity RORα and RORγ inverse activity, potentially explaining its effectiveness in various TH17-mediated autoimmune disease models. However, recent studies suggest that in conjunction with the RORs, LXR mediates a negative regulatory effect on TH17 cell differentiation. Since T09 acts on both LXRs and RORs, it presents as a valuable tool to understand how compounds with mixed pharmacology affect potential pathological cell types. Therefore, using T09, we investigated the mechanism by which the LXRs and RORs affect TH17 cell differentiation and function. Here we demonstrate that T09 activity at RORα and γ, not LXR, is facilitating the inhibition of TH17 cell differentiation and function. We also demonstrate that LXR activity inhibits the differentiation and function of TH1, TH2 and iTreg cells. Finally, T09 inhibited T cell proliferation and induced cell death. These data help explain much of the efficacy of T09 in inflammatory models and suggest that the generation of synthetic ligands with graded, combined LXR and ROR activity may hold utility in the treatment of inflammatory and autoimmune diseases where targeting both TH17 and TH1 cells is required. © 2012 Solt et al.