Year: 2017
Type: dissertation
Abstract: Multiple sclerosis (MS) is an autoimmune disease that targets the central nervous system (CNS). Interferon (IFN)-β was the first approved therapy for relapsing-remitting MS more than 20 years ago, however, its mechanism of action remains ill-defined. Using a myelin oligodendrocyte glycoprotein (MOG)-induced murine experimental autoimmune encephalomyelitis (EAE) model for MS, our earlier studies identified that IFN-β-/- mice exhibit an earlier onset and a more rapid progression of disease compared to IFN-β+/+ mice. CD4+ T cells, specifically of the Th17 lineage, are posited to be pathogenic in MS and in EAE, and CD11c+ dendritic cells (DCs) are critical antigen-presenting cells that have the potential to regulate pathogenic T cells in MS and EAE. Accordingly, we investigated the immunoregulatory effects of IFN-β on CD4+ T cells and DCs. Our studies revealed that CD4+ T cells isolated from IFN-β-/- mice are primed to polarize to the Th17 lineage, associated with expression of Th17-associated cytokine receptors. Stimulation with a cocktail of Th17-inducing cytokines led to increased expression of Th17-associated genes in IFN-β-/- Th17 cells compared to IFN-β+/+ Th17 cells, suggestive of a regulatory role for IFN-β in determining the Th17 cell transcriptome. Consistent with these findings, we observed a greater proportion of Th17 cells in the LNs of IFN-β-/- mice compared with IFN-β+/+ mice during EAE, with increased numbers of CD4+ T cells in the CNS of IFN-β-/- mice, regardless of stage of disease. We identified that IFN-β exerts immunoregulatory effects on DCs, associated with determining cytokine production and expression of co-stimulatory activation markers. IFN-β-/- DCs drive increased proliferation of MOG-transgenic CD4+ T cells, and produce more IL-6 and IL-23, critical for induction of Th17 cells. Finally, we provide evidence that IFN-β regulates the migration of DCs into the CNS during EAE, by modulating STAT1-dependent CCR7 expression. 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.
Source: TSpace (University of Toronto)
Author: Leesa M. Pennell
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2787297315