Expression and function of IL-1 receptor type 2 (IL-1RII) regulating human Th17 responses

Abstract

Abstract Th17 cells are a unique subset of proinflammatory cells conferring protection against extracellular bacteria and fungi, but have been also implicated in the pathogenesis of many autoimmune diseases. IL-1β is critical for the differentiation, expansion, in vivo survival, and effector function of Th17 cells. Among components of IL-1 receptor (IL-1R), decoy IL-1RII is a negative regulator of functional IL-1RI-mediated IL-1β signaling. Given its preferential expression on Treg cells, IL-1RII has been suggested to play a role for controlling the Th17 and Treg balance. However, little is known about a molecular mechanism underlying IL-1RII expression and its contribution to modulation of Th17 responses. Here, we found that IL-1RI and IL-1RII expression were rapidly induced by memory CD4+ T cells after stimulation with TCR alone. Cyclosporin A reduced IL-1RII expression, whereas an augmented FOXP3 was associated with enhanced IL-1RII expression. This finding was corroborated by in vitro assays using NFAT inhibitor, dNP2-VIVIT and an inhibitor of FOXP3/NFAT1 interaction, peptide FOXP3 393–403. Moreover, reporter assay suggests that NFAT/FOXP3 binding sites in IL-1RII promoter are critical for its transcription. At day 2 post-stimulation, there were three distinct subsets; IL-1RI+IL-1RII−, IL-1RI+IL-1RII+, and IL- 1RI−IL-1RII− CD4+ T cells, having unique features including cytokine production profile, the expression of Tregassociated genes, and responsiveness to IL-1β, suggesting a pivotal regulatory role of IL-1RII for human Th17 responses. Our findings will be beneficial to understanding a modulatory mechanism on Th17 response and IL- 1β-mediated IL-1R signaling contributing to pathogenesis of autoimmune diseases.