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

Gerd Meyer Zu Horste; Chuan Wu; Chao Wang; Le Cong; Mathias Pawlak; Youjin Lee; Wassim Elyaman; Sheng Xiao; Aviv Regev; Vijay K Kuchroo

doi:10.1016/j.celrep.2016.05.088

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

Cell Rep. 2016 Jul 12;16(2):392-404. doi: 10.1016/j.celrep.2016.05.088. Epub 2016 Jun 23.

Authors

Affiliations

¹ 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.
² The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
³ Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215, USA.
⁴ 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.

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.

Keywords: IL-23R; Notch; RBPJ; Th17 cells; pathogenicity.

Published by Elsevier Inc.

MeSH terms

Animals
Binding Sites
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism*
Gene Expression
Gene Expression Regulation / immunology
Immunoglobulin J Recombination Signal Sequence-Binding Protein / physiology*
Interleukin-10 / biosynthesis
Mice, 129 Strain
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins c-maf / physiology
Receptors, Interleukin / genetics*
Receptors, Interleukin / metabolism
Th17 Cells / metabolism*
Transcriptional Activation

Substances

Immunoglobulin J Recombination Signal Sequence-Binding Protein
Maf protein, mouse
Nuclear Receptor Subfamily 1, Group F, Member 3
Proto-Oncogene Proteins c-maf
Rbpj protein, mouse
Receptors, Interleukin
interleukin-23 receptor, mouse
Interleukin-10

Abstract

MeSH terms

Substances

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