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CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells.

Nature communications (2015-10-30)
Ervin E Kara, Duncan R McKenzie, Cameron R Bastow, Carly E Gregor, Kevin A Fenix, Abiodun D Ogunniyi, James C Paton, Matthias Mack, Diana R Pombal, Cyrill Seillet, Bénédicte Dubois, Adrian Liston, Kelli P A MacDonald, Gabrielle T Belz, Mark J Smyth, Geoffrey R Hill, Iain Comerford, Shaun R McColl
ABSTRACT

IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.

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