Non-redundant requirement for CXCR3 signaling for effective treatment of CNS autoimmunity with type I interferon

• Published in: The Journal of immunology (1950) Vol. 202; no. 1_Supplement; pp. 193 - 193.7
• Main Authors: Chen, Jun, Chong, Wai Po, Wang, WeiWei, Li, Chunmei, Gery, Igal, Caspi, Rachel R
• Format: Journal Article
• Language: English
• Published: 01.05.2019
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.202.Supp.193.7

Abstract Type I interferons (IFNs) have shown therapeutic potential in treating CNS autoimmune diseases (IFN-β for multiple sclerosis and IFN-α for uveitis), but treatment is not always effective. Here, we describe a non-redundant requirement for GαI-coupled CXCR3 in the immunomodulatory actions of type I IFNs that culminates in the suppression of human uveitis and experimental autoimmune uveitis (EAU). Effective treatment with IFN-α/β inhibited autopathogenic CD4+ T cell migration to effector sites in mice by upregulating expression of the cognate ligands CXCL9, CXCL10 and CXCL11, causing ligand-mediated downregulation of CXCR3 expression and effector T cell retention in the spleen. These effects of IFN-α/β also required IFN-γ. In the absence of CXCR3, type I IFNs were ineffective in treating active EAU. In patients with uveitis, disease exacerbations associated with reduced serum IFN-α concentrations. Importantly, IFN-α/β reduced CXCR3 expression and human effector T cell migration, and these parameters markedly associated with IFN-α therapeutic efficacy in uveitis patients. Our findings provide new insights into the molecular basis of type I IFN therapy for CNS autoimmune diseases and identify CXCR3 as a critical biomarker for effective immunotherapy with type I IFNs.