title: Innate IFN-γ promotes development of experimental autoimmune encephalomyelitis: a role for NK cells and M1 macrophages.
abstract: The role of IFN-γ in the pathogenesis of autoimmune diseases is controversial. Although Th1 cells can induce experimental autoimmune encephalomyelitis (EAE), IFN-γ can suppress Th17 cells that are pathogenic in EAE. Here we show that NK cells provide an early source of IFN-γ during development of EAE. Depletion of NK cells or neutralization of IFN-γ delayed the onset of EAE and was associated with reduced infiltration of IL-17(+) and GM-CSF(+) T cells into the CNS. In the passive transfer model, immune cells from myelin oligodendrocyte glycoprotein (MOG)-immunized IFN-γ(-/-) mice failed to induce EAE, despite producing IL-17 and GM-CSF. The macrophages expressed markers of M2 activation and the T cells had low very late antigen-4 (VLA-4) expression and failed to infiltrate the CNS. Addition of recombinant IFN-γ to immune cells from the IFN-γ(-/-) mice activated M1 macrophages and restored VLA-4 expression, migratory, and encephalitogenic activity of T cells. Furthermore, treatment of recipient mice with anti-VLA-4 neutralizing antibody abrogated EAE induced by transfer of T cells from WT mice. Our findings demonstrate IFN-γ-producing T cells are not required for development of EAE, but NK cell-derived IFN-γ has a key role in promoting M1 macrophage expansion and VLA-4-mediated migration of encephalitogenic T cells into the CNS.
authors: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors: Lara S
authors: LS
authors: Dungan
authors: Niamh C
authors: NC
authors: McGuinness
authors: Louis
authors: L
authors: Boon
authors: Marina A
authors: MA
authors: Lynch
authors: Kingston H G
authors: KH
authors: Mills
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D007371:Interferon-gamma
keywords: EAE; IFN-γ; Macrophage; NK cells; T cells