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Sci Rep. 2016 Dec 15;6:39117. doi: 10.1038/srep39117.

Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner.

Author information

1
Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Switzerland.
2
Department of Fundamental Oncology, Ludwig Center for Cancer Research, University of Lausanne, Switzerland.
3
Institut Pasteur, INSERM U1224, Microenvironment and Immunity Unit, Paris, France.
4
Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute of Experimental Cancer Research, Lausanne, Switzerland.

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.

PMID:
27974744
PMCID:
PMC5156918
DOI:
10.1038/srep39117
[Indexed for MEDLINE]
Free PMC Article

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