3 years ago

Interferon-β regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis

Interferon-β regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis
Leesa M. Pennell, Eleanor N. Fish
CD11c+ dendritic cells (DCs) exert a critical role as antigen-presenting cells in regulating pathogenic T cells in multiple sclerosis (MS). To determine whether the therapeutic benefit of interferon-β (IFN-β) treatment for MS is in part influenced by IFN regulation of DC function, we examined the immunophenotype of DCs derived from IFN-β+/+ and IFN-β−/− mice using a myelin oligodendrocyte glycoprotein (MOG) peptide-induced mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our earlier work identified that IFN-β−/− mice exhibit earlier onset and more rapid progression of neurological impairment compared with IFN-β+/+ mice. In this study we show that lipopolysaccharide-/MOG peptide-stimulated IFN-β−/− DCs secrete cytokines associated with pathological T helper type 17 rather than regulatory T-cell polarization and exhibit increased CD80 and MHCII expression when compared with stimulated IFN-β+/+ DCs. IFN-β−/− DCs from mice immunized to develop EAE induce greater proliferation of MOG-transgenic CD4+ T cells and promote interleukin-17 production by these T cells. Adoptive transfer of MOG peptide-primed IFN-β−/− DCs into IFN-β+/+ and IFN-β−/− mice immunized to develop EAE resulted in their rapid migration into the central nervous system of recipient mice, before onset of disease, which we attribute to failed signal transducer and activator of transcription 1-mediated inhibition of CCR7. Taken together, our data support immunoregulatory roles for IFN-β in the activation and migration of DCs during EAE. Dendritic cells (DCs) exert a critical role as antigen-presenting cells in regulating pathogenic T cells in multiple sclerosis (MS). Following stimulation, DCs derived from IFN-β–/– mice secrete cytokines associated with pathological Th17 rather than Treg polarization and induce enhanced proliferation of MOG-transgenic CD4+ T cells. Adoptive transfer of MOG-peptide primed IFN-β–/– DCs into IFN-β+/+ and IFN-β–/– mice immunized to develop EAE, a mouse model for MS, resulted in their rapid migration into the central nervous system of recipient mice, before onset of disease, indicative of a role for IFN-β in the activation and migration of DCs during MS.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/imm.12781

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