RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression

• Main Authors: Meyer zu Horste, Gerd (Author), Wu, Chuan (Author), Wang, Chao (Author), Cong, Le (Author), Pawlak, Mathias (Author), Lee, Youjin (Author), Elyaman, Wassim (Author), Xiao, Sheng (Author), Regev, Aviv (Contributor), Kuchroo, Vijay K (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2017-04-18T20:30:56Z.
• Subjects: Article
• Online Access: Get fulltext

Interleukin-17 (IL-17)-producing helper T cells (Th17 cells) play an important role in autoimmune diseases. However, not all Th17 cells induce tissue inflammation or autoimmunity. Th17 cells require IL-23 receptor (IL-23R) signaling to become pathogenic. The transcriptional mechanisms controlling the pathogenicity of Th17 cells and IL-23R expression are unknown. Here, we demonstrate that the canonical Notch signaling mediator RBPJ is a key driver of IL-23R expression. In the absence of RBPJ, Th17 cells fail to upregulate IL-23R, lack stability, and do not induce autoimmune tissue inflammation in vivo, whereas overexpression of IL-23R rescues this defect and promotes pathogenicity of RBPJ-deficient Th17 cells. RBPJ binds and trans-activates the Il23r promoter and induces IL-23R expression and represses anti-inflammatory IL-10 production in Th17 cells. We thus find that Notch signaling influences the development of pathogenic and non-pathogenic Th17 cells by reciprocally regulating IL-23R and IL-10 expression.