title: Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals.
abstract: Two models are proposed to explain Notch function during helper T (Th) cell differentiation. One argues that Notch instructs one Th cell fate over the other, whereas the other posits that Notch function is dictated by cytokines. Here we provide a detailed mechanistic study investigating the role of Notch in orchestrating Th cell differentiation. Notch neither instructed Th cell differentiation nor did cytokines direct Notch activity, but instead, Notch simultaneously regulated the Th1, Th2, and Th17 cell genetic programs independently of cytokine signals. In addition to regulating these programs in both polarized and nonpolarized Th cells, we identified Ifng as a direct Notch target. Notch bound the Ifng CNS-22 enhancer, where it synergized with Tbet at the promoter. Thus, Notch acts as an unbiased amplifier of Th cell differentiation. Our data provide a paradigm for Notch in hematopoiesis, with Notch simultaneously orchestrating multiple lineage programs, rather than restricting alternate outcomes.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Bailis
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.forename: Terry C
authors.initials: TC
authors.lastname: Fang
authors.forename: Robin D
authors.initials: RD
authors.lastname: Hatton
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006790:Host-Parasite Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D051881:Receptor, Notch1 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014258:Trichuris / Q000276:immunology / Q000502:physiology
chemical_list: D016207:Cytokines; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D007371:Interferon-gamma
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