title: Notch signaling regulates mouse and human Th17 differentiation.
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.
authors.affiliation: Molecular Biology Program, Loyola University Medical Center, Maywood, IL 60153, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Keerthivasan
authors.forename: Reem
authors.initials: R
authors.lastname: Suleiman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lawlor
authors.forename: Justine
authors.initials: J
authors.lastname: Roderick
authors.forename: Tonya
authors.initials: T
authors.lastname: Bates
authors.forename: Lisa
authors.initials: L
authors.lastname: Minter
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
authors.forename: Ignacio
authors.initials: I
authors.lastname: Juncadella
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: I Caroline
authors.initials: IC
authors.lastname: Le Poole
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1