Functionally distinct IFN‐γ+IL‐17A+ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

• Published in: European journal of immunology Vol. 50; no. 12; pp. 1941 - 1951
• Main Authors: Chen, Yi‐Hsing, Eskandarpour, Malihe, Gondrand, Aurelia, Zhang, Xiaozhe, Gu, Renyang, Galatowicz, Grazyna, Lightman, Sue L., Calder, Virginia L.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.12.2020
• Subjects: Animals; Autoimmune Diseases - immunology; CCR6 protein; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell migration; Cell Movement - immunology; Cells, Cultured; Chemokines; CXCR3 protein; Dexamethasone; Disease Models, Animal; Endothelium; Experimental autoimmune uveitis; Experimental autoimmune uveoretinitis; Female; Helper cells; Humans; IL‐17A+IFN‐γ; Interferon; Interferon-gamma - immunology; Interleukin-17 - immunology; Lymphocytes T; Mice; Mice, Inbred C57BL; Retina; steroid resistance; T cell migration; Th1 Cells - immunology; Th17 Cells - immunology; Th17/Th1 cells; Uveitis; steroid resistance; Th17/Th1 cells; experimental autoimmune uveitis; IL-17A+IFN-γ; T cell migration
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202048616

Immunopathogenic roles for both Th1 (CD4+IFN‐γ+) and Th17 (CD4+IL‐17A+) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4+ T cells co‐expressing IFN‐γ and IL‐17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid‐binding protein peptide‐induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.6 ± 4.2%) and draining LNs (mean 8.4 ± 3.9%; p = 0.01) relative to controls. Topical dexamethasone treatment effectively reduced EAU severity and decreased retinal Th1 cells (p = 0.01), but had no impact on retinal Th17/Th1 or Th17 cells compared to saline controls. Using in vitro migration assays with mouse CNS endothelium, we demonstrated that Th17/Th1 cells were significantly increased within the migrated population relative to controls (mean 15.6 ± 9.5% vs. 1.9 ± 1.5%; p = 0.01). Chemokine receptor profiles of Th17/Th1 cells (CXCR3 and CCR6) did not change throughout the transendothelial migration process and were unaffected by dexamethasone treatment. These findings support a role for Th17/Th1 cells in EAU and their resistance to steroid inhibition suggests the importance of targeting both Th17 and Th17/Th1 cells for improving therapy. Both Th1 and Th17 cells can induce experimental autoimmune uveitis (EAU). A third subset (Th17/Th1 cells) was found to be elevated in the retina during EAU. These cells expressed transcription factors Tbet and RORγt and secreted both IFN‐γ and IL‐17A. Their existence indicated heterogeneity of retinal CD4+ T‐cell subsets. While Th1 cells were susceptible to inhibition by dexamethasone, both Th17 and Th17/Th1 cells were steroid resistant.