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

• Published in: Cell reports (Cambridge) Vol. 16; no. 2; pp. 392 - 404
• Main Authors: Meyer zu Horste, Gerd, Wu, Chuan, Wang, Chao, Cong, Le, Pawlak, Mathias, Lee, Youjin, Elyaman, Wassim, Xiao, Sheng, Regev, Aviv, Kuchroo, Vijay K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2016; Elsevier
• Subjects: Animals; Binding Sites; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Gene Expression; Gene Expression Regulation - immunology; IL-23R; Immunoglobulin J Recombination Signal Sequence-Binding Protein - physiology; Interleukin-10 - biosynthesis; Mice, 129 Strain; Mice, Inbred C57BL; Notch; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; pathogenicity; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-maf - physiology; RBPJ; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; Th17 cells; Th17 Cells - metabolism; Transcriptional Activation; pathogenicity; IL-23R; RBPJ; Notch; Th17 cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.088

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. [Display omitted] •RBPJ promotes experimental CNS autoimmunity via the IL-23R•RBPJ-deficient Th17 cells fail to express IL-23R and related transcripts•RBPJ binds and trans-activates the Il23r promoter together with RORγt•RBPJ represses expression of IL-10 in Th17 cells Meyer zu Horste et al. find that RBPJ promotes the pathogenicity of Th17 cells by directly enhancing expression of the interleukin-23 receptor and repressing interleukin-10 production.