Suppression of T(H)17 Differentiation and Autoimmunity by a Synthetic ROR Ligand

T helper cells that produce Interleukin-17 (IL-17) (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases(1–3). The nuclear receptors retinoic acid receptor-related orphan receptors α and γt (RORα and RORγt) have indispensible roles in the development of this cell type(4–7). Here we present a first-in-class, high-affinity synthetic ligand, SR1001, specific to both RORα and RORγt that inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand binding domains (LBDs) of RORα and RORγt inducing a conformational change within the LBD that encompasses repositioning of helix 12 leading to diminished affinity for coactivators and increased affinity for corepressors resulting in suppression of the receptors transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells as demonstrated by inhibition of IL-17A gene expression and protein production. Additionally, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Thus, our data demonstrates the feasibility of targeting the orphan receptors RORα and RORγt to specifically inhibit T(H)17 cell differentiation and function and indicates that this novel class of compound has potential utility in the treatment of autoimmune diseases.