Abstract
IL-17-producing CD4(+)Th17 cells, CD8(+)Tc17 cells, and gamma delta T cells play critical roles in the pathogenesis of autoimmune psoriasis. ROR gamma t is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective ROR gamma t inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe ROR gamma t-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse gamma delta T cells. IL-23-induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of ROR gamma t in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that ROR gamma t inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by gamma delta T cells and CD8(+) Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23-induced IL-17A expression. Thus, ROR gamma t is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.