title: RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer Zu Horste
authors.affiliation: 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.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Cong
authors.affiliation: 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.
authors.forename: Mathias
authors.initials: M
authors.lastname: Pawlak
authors.affiliation: 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.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.affiliation: 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.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: 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. Electronic address: vkuchroo@evergrande.hms.harvard.edu.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D001665:Binding Sites; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051257:Proto-Oncogene Proteins c-maf / Q000502:physiology; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C495608:Maf protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051257:Proto-Oncogene Proteins c-maf; C497571:Rbpj protein, mouse; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse; D016753:Interleukin-10
keywords: IL-23R; Notch; RBPJ; Th17 cells; pathogenicity