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

摘要

Type I interferons (IFNs) have therapeutic potential inCNS autoimmune diseases, such as uveitis, but themolecular mechanisms remain unclear. Using aT cell-transfer model of experimental autoimmuneuveitis (EAU), we found that IFN-a/b treatment inhibitedthe migration of IFN-g-producing pathogenicCD4+ T cells to effector sites. IFN-a/b upregulatedthe expression of the cognate ligands CXCL9,CXCL10, and CXCL11, causing ligand-mediateddownregulation of CXCR3 expression and effectorT cell retention in the spleen. Accordingly, type IIFN did not alter EAU progression in CXCR3 / mice. In uveitis patients, disease exacerbationscorrelated with reduced serum IFN-a concentrations.IFN-a/b reduced CXCR3 expression andmigration by human effector T cells, and these parameterswere associated with the therapeutic effi-cacy of IFN-a in uveitis patients. Our findings provideinsight into the molecular basis of type I IFN therapyfor CNS autoimmune diseases and identify CXCR3as a biomarker for effective type I IFN immunotherapy.