CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells.
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.
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Ervin E
EE
Kara
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Duncan R
DR
McKenzie
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Cameron R
CR
Bastow
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Carly E
CE
Gregor
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Kevin A
KA
Fenix
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.|Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Abiodun D
AD
Ogunniyi
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.|Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
James C
JC
Paton
Department of Internal Medicine II, University Hospital Regensburg, Regensburg 93042, Germany.
Matthias
M
Mack
Department of Microbiology and Immunology, VIB and University of Leuven, B-3000 Leuven, Belgium.
Diana R
DR
Pombal
Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Cyrill
C
Seillet
Department of Neurosciences, KU-Leuven-University of Leuven, B-3000 Leuven, Belgium.
Bénédicte
B
Dubois
Department of Microbiology and Immunology, VIB and University of Leuven, B-3000 Leuven, Belgium.
Adrian
A
Liston
QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
Kelli P A
KPA
MacDonald
Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Gabrielle T
GT
Belz
QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.|School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
Mark J
MJ
Smyth
QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.|The Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
Geoffrey R
GR
Hill
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Iain
I
Comerford
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.|Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
Shaun R
SR
McColl
D000818:Animals; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology*; D054399:Receptors, CCR6 / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
C498126:CCR6 protein, mouse; C515335:Ccr2 protein, mouse; C491198:Eomes protein, mouse; D053759:Interleukin-23; D054390:Receptors, CCR2; D054399:Receptors, CCR6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor