Meyer Zu Horste Gerd, Wu Chuan, Wang Chao, Cong Le, Pawlak Mathias, Lee Youjin, Elyaman Wassim, Xiao Sheng, Regev Aviv, Kuchroo Vijay K
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215, USA.
The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Cell Rep. 2016 Jul 12;16(2):392-404. doi: 10.1016/j.celrep.2016.05.088. Epub 2016 Jun 23.
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.
产生白细胞介素-17（IL-17）的辅助性T细胞（Th17细胞）在自身免疫性疾病中起重要作用。然而，并非所有Th17细胞都会引发组织炎症或自身免疫。Th17细胞需要白细胞介素-23受体（IL-23R）信号传导才能致病。控制Th17细胞致病性和IL-23R表达的转录机制尚不清楚。在此，我们证明经典Notch信号传导介质RBPJ是IL-23R表达的关键驱动因素。在缺乏RBPJ的情况下，Th17细胞无法上调IL-23R，缺乏稳定性，并且在体内不会引发自身免疫组织炎症，而IL-23R的过表达可挽救此缺陷并促进RBPJ缺陷型Th17细胞的致病性。RBPJ结合并反式激活Il23r启动子，诱导IL-23R表达，并抑制Th17细胞中抗炎性IL-10的产生。因此，我们发现Notch信号通过相互调节IL-23R和IL-10的表达来影响致病性和非致病性Th17细胞的发育。
