title: IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development.
abstract: Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis.
authors.affiliation: *Inflammation Research Group, Transgenic Technology Laboratory, Hellenic Pasteur Institute, Athens, Greece
authors.forename: Nadia
authors.initials: N
authors.lastname: Kavrochorianou
authors.affiliation: †Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
authors.forename: Maria
authors.initials: M
authors.lastname: Evangelidou
authors.affiliation: *Inflammation Research Group, Transgenic Technology Laboratory, Hellenic Pasteur Institute, Athens, Greece
authors.forename: Melina
authors.initials: M
authors.lastname: Markogiannaki
authors.affiliation: ‡Laboratory of Biotechnology and Applied Pharmacology Ecole Normale Supérieure de Cachan, Cachan, France
authors.forename: Michael
authors.initials: M
authors.lastname: Tovey
authors.affiliation: §Department of Biological Applications and Technology, University of Ioannina, Ioannina, Greece|Correspondence: G.T., Dept. of Biological Applications and Technology, University of Ioannina, 45110 Ioannina, Greece. E-mail: gthyfron@uoi.gr
authors.forename: George
authors.initials: G
authors.lastname: Thyphronitis
authors.affiliation: *Inflammation Research Group, Transgenic Technology Laboratory, Hellenic Pasteur Institute, Athens, Greece|Correspondence: S.H., Inflammation Research Group, Transgenic Technology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece. E-mail: sharalambous@pasteur.gr
authors.forename: Sylva
authors.initials: S
authors.lastname: Haralambous
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental; D015870:Gene Expression; D020869:Gene Expression Profiling; D007370:Interferon Type I / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D009928:Organ Specificity / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D053633:Receptor, Interferon alpha-beta
keywords: MS; T cells; cytokine receptors; inflammation; transgenic mice