1. CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells
- Author
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Cyrill Seillet, James C. Paton, Diana Pombal, Mark J. Smyth, Ervin E. Kara, Abiodun D. Ogunniyi, Cameron R. Bastow, Kevin A. Fenix, Carly E. Gregor, Adrian Liston, Kelli P. A. MacDonald, Matthias Mack, Bénédicte Dubois, Iain Comerford, Gabrielle T. Belz, Geoffrey R. Hill, Duncan R. McKenzie, Shaun R. McColl, Kara, Ervin E, McKenzie, Duncan R, Bastow, Cameron R, Gregor, Carly E, Fenix, Kevin A, Ogunniyi, Abiodun D, Paton, James C, Mack, Matthias, Pombal, Diana R, Seillet, Cyrill, Dubois, Bénédicte, Liston, Adrian, MacDonald, Kelli PA, Belz, Gabrielle T, Smyth, Mark J, Hill, Geoffrey R, Comerford, Iain, and McColl, Shaun R
- Subjects
Receptors, CCR6 ,Encephalomyelitis, Autoimmune, Experimental ,Receptors, CCR2 ,Cellular differentiation ,General Physics and Astronomy ,Inflammation ,chemical and pharmacologic phenomena ,Biology ,Interleukin-23 ,General Biochemistry, Genetics and Molecular Biology ,immune response ,Article ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Interleukin 23 ,medicine ,Animals ,Humans ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Experimental autoimmune encephalomyelitis ,Granulocyte-Macrophage Colony-Stimulating Factor ,hemic and immune systems ,Cell Differentiation ,General Chemistry ,medicine.disease ,bacterial disease ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Granulocyte macrophage colony-stimulating factor ,Tumor Necrosis Factors ,Interleukin 12 ,gene expression ,Th17 Cells ,Tumor necrosis factor alpha ,medicine.symptom ,T-Box Domain Proteins ,030215 immunology ,Homing (hematopoietic) ,medicine.drug ,pathogen - 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., Little is known regarding migration of Th17 cells that produce distinct cytokines implicated in protection and pathology. Kara et al. show that a switch from CCR6 to CCR2 by Th17 cells defines a signature (CCR6−CCR2+) of GM-CSF+ Th17 cells and drives pathology in a mouse model of autoimmunity.
- Published
- 2015