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Jun Chen, Chunmei Li, Weiwei Wang, Zilin Chen, Ying Chen, Hongyan Zhou, Wai Po Chong, Igal Gery, Rachel R Caspi; Non-redundant requirement for CXCR3 signaling for effective treatment of eye-specific autoimmunity with type I IFNs. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2537.
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Type I interferons (IFNs) have shown therapeutic potential in treating central nervous system (CNS) autoimmune diseases, e.g. IFN-β for multiple sclerosis and IFN-α for uveitis. However, treatment is not always effective in patients, and the molecular mechanisms by which type I IFNs exert their immunomodulatory functions remain largely unknown.
To address this question we examined the modulatory effects of type I IFNs in mouse models of experimental autoimmune uveitis (EAU) and T cell-transfer model of experimental uveitis (Chen et al. J Immunol 2006), as well as in PBMCs of patients with autoimmune uveitis. Autopathogenic T cells were detected and tracked in mice with a clonotypic antibody.
Effective treatment with type I IFNs 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 type I IFNs also required IFN-γ. In the absence of CXCR3, type I IFNs were ineffective in active EAU. In patients with uveitis, disease exacerbations correlated with reduced serum IFN-α concentrations. Importantly, type I IFNs inhibited CXCR3 expression and human effector T cell migration, and these parameters markedly correlated with IFN-α therapeutic efficacy in uveitis patients.
We demonstrate 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 EAU. 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.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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