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.
Highlights
IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens and drive numerous autoimmune diseases
We demonstrate that CCR2, not CCR6, is a key driver of encephalitogenic T-helper 17 (Th17) cell recruitment into the central nervous system (CNS)
To identify CCR6-independent mechanisms mediating recruitment of Th17 cells and to compare migratory potential of Th17 and Tregs, we screened for the expression of all known chemokine receptors in CCR6 þ and CCR6 À subsets of Tregs from B6.Foxp3GFP mice and IL-17A-eYFP þ CD4 þ T cells from B6.Il17aCreRosa26eYFP mice, in which Cre recombinase is driven by Il17a promoter activity to permanently mark cells that are currently producing or have previously expressed IL-17A (IL-17A þ /ex) with enhanced yellow fluorescent protein[11] (Supplementary Fig. 1)
Summary
IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens and drive numerous autoimmune diseases. 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 À CCR2 þ ) of GM-CSF/IFNg-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Th17 cells with an IL-10 þ and IL-9 þ cytokine profile, consistent with published descriptions of Th17 cells of more limited pathogenic potential, bear a CCR6 þ CCR2 þ phenotype in vivo Using these signatures, we demonstrate that an IL-23/IL-1/IFNg/tumour necrosis factor-a (TNFa)/T-bet/Eomesodermin-driven circuit drives GM-CSF/IFNg-producing Th17 cell development in vivo. We report a unique cell surface signature and novel developmental features of GM-CSF/IFNg-producing Th17 cells in vivo and resolve the outstanding question regarding the molecular control of encephalitogenic Th17 cell trafficking to the CNS in EAE
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