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

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-alpha/beta treatment inhibited the migration of IFN-gamma-producing pathogenic CD4(+) T cells to effector sites. IFN-alpha/beta 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-alpha concentrations. IFN-alpha/beta reduced CXCR3 expression and migration by human effector T cells, and these parameters were associated with the therapeutic efficacy of IFN-alpha 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.