Notch signaling regulates mouse and human Th17 differentiation

Shilpa Keerthivasan, Reem Suleiman, Rebecca Lawlor, Justine Roderick, Tonya Bates, Lisa Minter, Juan Anguita, Ignacio Juncadella, Brian J. Nickoloff, I. Caroline Le Poole, Lucio Miele*, Barbara A. Osborne

*Corresponding author for this work

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Th17 cells are known to play a critical role in adaptive immune responses to several important extracellular pathogens. Additionally, Th17 cells are implicated in the pathogenesis of several autoimmune and inflammatory disorders as well as in cancer. Therefore, it is essential to understand the mechanisms that regulate Th17 differentiation. Notch signaling is known to be important at several stages of T cell development and differentiation. In this study, we report that Notch1 is activated in both mouse and human in vitro-polarized Th17 cells and that blockade of Notch signaling significantly downregulates the production of Th17-associated cytokines, suggesting an intrinsic requirement for Notch during Th17 differentiation in both species. We also present evidence, using promoter reporter assays, knockdown studies, as well as chromatin immunoprecipitation, that IL-17 and retinoic acid-related orphan receptor γt are direct transcriptional targets of Notch signaling in Th17 cells. Finally, in vivo inhibition of Notch signaling reduced IL-17 production and Th17-mediated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Thus, this study highlights the importance of Notch signaling in Th17 differentiation and indicates that selective targeted therapy against Notch may be an important tool to treat autoimmune disorders, including multiple sclerosis.

Original languageEnglish (US)
Pages (from-to)692-701
Number of pages10
JournalJournal of Immunology
Volume187
Issue number2
DOIs
StatePublished - Jul 15 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Keerthivasan, S., Suleiman, R., Lawlor, R., Roderick, J., Bates, T., Minter, L., Anguita, J., Juncadella, I., Nickoloff, B. J., Le Poole, I. C., Miele, L., & Osborne, B. A. (2011). Notch signaling regulates mouse and human Th17 differentiation. Journal of Immunology, 187(2), 692-701. https://doi.org/10.4049/jimmunol.1003658