title: Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner.
abstract: Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function.
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Coutaz
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Switzerland.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Hurrell
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Switzerland.
authors.forename: Floriane
authors.initials: F
authors.lastname: Auderset
authors.affiliation: Department of Fundamental Oncology, Ludwig Center for Cancer Research, University of Lausanne, Switzerland.
authors.forename: Haiping
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Fundamental Oncology, Ludwig Center for Cancer Research, University of Lausanne, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Siegert
authors.affiliation: Institut Pasteur, INSERM U1224, Microenvironment and Immunity Unit, Paris, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Department of Fundamental Oncology, Ludwig Center for Cancer Research, University of Lausanne, Switzerland.
authors.forename: Ping-Chih
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute of Experimental Cancer Research, Lausanne, Switzerland.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D007114:Immunization / Q000379:methods*; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000166:cytology*
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D020381:Interleukin-17; D051880:Receptors, Notch; D011990:Receptors, Transferrin