The Wnt inhibitor secreted Frizzled-Related Protein 1 (sFRP1) promotes human Th17 differentiation.

Wnt/ß-catenin signaling plays a crucial role during embryogenesis and tumorigenesis, and in T cells, promotes the differentiation of Th2 cells. However, the role of Wnt signals in the differentiation and maintenance of human Th17 cells remains poorly understood. We found that the higher levels of IL-17 in the synovial fluid of rheumatoid arthritis (RA) patients compared with that of osteoarthritis (OA) patients were associated with a higher concentration of sFRP1 (secreted Frizzled-Related Protein 1), an inhibitor of the Wnt/ß-catenin pathway. The addition of sFRP1 during TCR-mediated stimulation induced a significant increase in IL-17 production by both naïve and memory CD4(+) T cells. Moreover, under Th17-differentiation conditions, the addition of sFRP1 significantly reduced the requirement for TGF-ß. Mechanistically, we observed that sFRP1 significantly enhanced the phosphorylation of Smad2/3 in CD4(+) T cells upon TGF-ß stimulation and that blocking TGF-ß signaling abolished the Th17-promoting activity of sFRP1. Our findings reveal a novel function for sFRP1 as a potent inducer of human Th17-cell differentiation. Consequently, sFRP1 may represent a promising target for the treatment of Th17-mediated disease in humans.