A Naturally Occurring, Soluble Antagonist of Human IL-23 Inhibits the Development and In Vitro Function of Human Th17 Cells

Abstract

Th17 CD4 cells are critical to inflammation. Their secretion of IL-17 drives inflammation in human diseases, including inflammatory bowel disease. Differentiation of mature Th17 cells depends on stimulation with IL-6, TGF-β, and IL-21 and the induction of RORγt, but IL-23 is essential to Th17 phenotype, stability, and function. Induction of Th17 cells can be antagonized by IL-4 or IFN-γ, but mechanisms through which terminal differentiation can be inhibited have not been identified. Human IL-23Rα (HuIL23Rα)-chain mRNA transcripts exist that lack exon 9 (“Δ9”); these are translated to a truncated receptor containing the entire external domain. This soluble variant of the HuIL23Rα-chain antagonizes Th17 maturation. It is secreted and present at low levels in the blood. It represents 10% of HuIL23Rα-chain mRNA, binds IL-23 in solution, and inhibits the phosphorylation of STAT3 caused by IL-23. In in vitro Th17 cell differentiation experiments, Δ9 inhibits the production of the Th17-associated cytokines IL-17A and IL-17F. Δ9 does not bind IL-12; thus, it is a specific inhibitor of IL-23 and a modulator of Th17 cells. Our results indicate that this soluble form of HuIL23Rα likely functions to regulate Th17 activity.