Interferon-β regulates Th17 polarization and dendritic cell migration in EAE — ASN Events
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  2. Poster Session 2
  3. Interferon-β regulates Th17 polarization and dendritic cell migration in EAE

Interferon-β regulates Th17 polarization and dendritic cell migration in EAE (#317)

Leesa M Pennell 1 2 , Eleanor N Fish 1 2
  1. Immunology, University of Toronto, Toronto, ON, Canada
  2. Toronto General Research Institute, University Health Network, Toronto, ON, Canada

To investigate the mechansim(s) of action of IFN-β in suppressing immune and inflammatory processes in multiple sclerosis (MS), we employ a myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE) model of MS in IFN-β+/+ and IFN-β-/- mice. IFN-β-/- mice exhibit earlier onset and more rapid progression of neurologic impairment compared with IFN-β+/+mice. We provide MRI evidence for a rapid influx of cells into the brains of IFN-β-/- mice with EAE: increased ventricle volume compared with IFN-β+/+ mice. Th17 cell numbers in the inguinal lymph nodes and in the CNS of IFN-β-/- mice with EAE are higher than for IFN-β+/+ mice, yet Treg numbers are lower. Anti-CD3/anti-CD28 antibody stimulation of whole splenocytes or CD4+ T cells from IFN-β-/- mice results in production of IL-17A, whereas identical stimulation of cells from IFN-β+/+ mice fails to increase IL-17A production. IFN-β-/- CD4+ T cells express higher levels of IRF-4 following anti-CD3/anti-CD28 antibody activation and increased expression of CCR6, IL-23R, IL-6R and CXCR4. Moreover, CD4+ T cells from IFN-β-/- mice exhibit a Th17 primed transcriptome. Increased Th17 cell polarization during EAE may be driven by dendritic cells (DCs), as DCs derived from IFN-β-/- mice induce greater proliferation of T cells derived from either IFN-β+/+ or IFN-β-/- mice, compared with DCs derived from IFN-β+/+mice. Additionally, IFN-β-/- DCs secrete cytokines associated with Th17 rather than Treg polarization. Adoptive transfer of MOG peptide-primed IFN-β-/- DCs into IFN-β+/+ and IFN-β-/- mice with EAE resulted in their rapid migration into the brains and spinal cords (CNS) of recipient mice, visualized by fluorescence imaging. FACS analysis of DCs isolated from naïve IFN-β-/- mice revealed increased expression CCR7, CXCR4, and MHCII upon TLR4 activation compared to IFN-β+/+ DCs. Taken together, our data indicate immunoregulatory roles for IFN-β in suppression of Th17 cells and in limiting the activation and trafficking of DCs during EAE.