Type I Interferon Therapy Limits CNS Autoimmunity by Inhibiting CXCR3-Mediated Trafficking of Pathogenic Effector T Cells

Abstract

Summary: Type I interferons (IFNs) have therapeutic potential in CNS autoimmune diseases, such as uveitis, but the molecular mechanisms remain unclear. Using a T cell-transfer model of experimental autoimmune uveitis (EAU), we found that IFN-α/β treatment inhibited the migration of IFN-γ-producing pathogenic CD4+ T cells to effector sites. IFN-α/β upregulated the expression of the cognate ligands CXCL9, CXCL10, and CXCL11, causing ligand-mediated downregulation of CXCR3 expression and effector T cell retention in the spleen. Accordingly, type I IFN did not alter EAU progression in CXCR3−/− mice. In uveitis patients, disease exacerbations correlated with reduced serum IFN-α concentrations. IFN-α/β reduced CXCR3 expression and migration by human effector T cells, and these parameters were associated with the therapeutic efficacy of IFN-α in uveitis patients. Our findings provide insight into the molecular basis of type I IFN therapy for CNS autoimmune diseases and identify CXCR3 as a biomarker for effective type I IFN immunotherapy. : The mechanisms by which type I IFN therapy limits CNS autoimmune diseases remain unclear. Using animal models of experimental autoimmune uveitis and uveitis patient samples, Wang et al. reveal that type I interferon therapy inhibits CXCR3-mediated effector T cell trafficking into uveitogenic eyes to decrease disease pathogenesis. Keywords: type I interferon, CXCR3, experimental autoimmune uveitis, human uveitis