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

Weiwei Wang; Wai Po Chong; Chunmei Li; Zilin Chen; Sihan Wu; Hongyan Zhou; Ying Wan; Wanjun Chen; Igal Gery; Yizhi Liu; Rachel R Caspi; Jun Chen

doi:10.1016/j.celrep.2019.06.021

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

Cell Rep. 2019 Jul 9;28(2):486-497.e4. doi: 10.1016/j.celrep.2019.06.021.

Authors

Weiwei Wang¹, Wai Po Chong², Chunmei Li¹, Zilin Chen¹, Sihan Wu¹, Hongyan Zhou¹, Ying Wan³, Wanjun Chen⁴, Igal Gery⁵, Yizhi Liu¹, Rachel R Caspi⁶, Jun Chen⁷

Affiliations

¹ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University (SYSU), Guangzhou 510060, China.
² State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University (SYSU), Guangzhou 510060, China; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
³ Biomedical Analysis Center, Third Military Medical University, Chongqing 40038, China.
⁴ Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
⁵ Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
⁶ Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA. Electronic address: caspir@nei.nih.gov.
⁷ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University (SYSU), Guangzhou 510060, China; Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA. Electronic address: chenjun35@mail.sysu.edu.cn.

Abstract

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.

Keywords: CXCR3; experimental autoimmune uveitis; human uveitis; type I interferon.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmune Diseases / genetics*
Humans
Immunotherapy / methods*
Interferon Type I / metabolism*
Mice
Receptors, CXCR3 / antagonists & inhibitors*
T-Lymphocytes / metabolism*

Substances

Cxcr3 protein, mouse
Interferon Type I
Receptors, CXCR3

Abstract

Publication types

MeSH terms

Substances

Grants and funding