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

Kara, EE;McKenzie, DR;Bastow, CR;Gregor, CE;Fenix, KA;Ogunniyi, AD;Paton, JC;Mack, M;Pombal, DR;Seillet, C;Dubois, B;Liston, A;MacDonald, KP;Belz, GT;Smyth, MJ;Hill, GR;Comerford, I;McColl, SR;

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/IFN-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/IFN-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFN/TNF/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFN-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/IFN-producing Th17 cells.