title: IL-12-polarized Th1 cells produce GM-CSF and induce EAE independent of IL-23.
abstract: CD4(+) T-helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL-23 is universally required for the acquisition of pathogenic properties by myelin-reactive T cells. We show that IL-12-modulated Th1 cells readily produce IFN-γ and GM-CSF in the CNS of mice and induce a severe form of EAE via an IL-23-independent pathway. Th1-mediated EAE is characterized by monocyte-rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL-23-modulated, stable Th17 cells induce EAE with a relatively mild course via an IL-12-independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4(+) T-helper-cell subsets and polarizing factors.
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI, USA.|Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Grifka-Walk
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI, USA.|Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.|Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Giles
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI, USA.|Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.|Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Segal
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009186:Myelin Sheath / Q000235:genetics / Q000276:immunology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: C515335:Ccr2 protein, mouse; D053759:Interleukin-23; D054390:Receptors, CCR2; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Experimental autoimmune encephalomyelitis; IL-12; IL-23; Th1 cells; Th17 cells