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

Abstract

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.

Overexpressing Kallistatin Aggravates Experimental Autoimmune Uveitis Through Promoting Th17 Differentiation

“…Interleukin 17 (IL-17) producing Th17 cells and IFN-gproducing Th1 cells, have been thought to be important in the immunopathogenesis of uveitis and EAU (8,13). The IFN-g + IL-17A + phenotype, named Th1/Th17 subset, is associated with Th17-mediated diseases in human and animal models (14). And it has been recently shown that CD4 + T cells or Th17 cells have substantial plasticity and display important functions in the tissue microenvironment during chronic inflammation (14)(15)(16)(17).…”

CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

“…It has been reported that Th17 cells have substantial plasticity and readily acquire ability to produce IFNγ in addition to IL-17 [15,38]. Our previous data suggested that the ability of Th17/Th1 cells to produce both IL-17 and IFNγ correlates with RORγt + and Tbet + transcription factor co-expression [36]. This subset, so-called Th17/Th1 cells, is thought to be due to Th17 cell plasticity, facilitated through IL-12 or IL-23 stimulation [39,40].…”

“…Human Th17/Th1 (IL-17 + IFNγ + ) cells are characterized by their expression of CD161, CCR6, IL-17 receptor E, RORC, and IL-4-induced gene 1 [38,42,43]. These Th17/Th1 cells are characterized by their resistance to corticosteroids in IRBP-induced EAU at peak disease, which may be due to a stable expression of multi-drug transporter type 1 (MDR1), an ATP-dependent membrane efflux pump [36]. It is supposed that Th17/Th1 cells lose their ability to produce IL-17 and become non-classical Th1 cells (expressing both RORγt and Tbet, but producing only IFNγ) following an IL-17/IFNγ double-producing phase [44].…”

“…In the monophasic and relapsing mice EAU models, Th1 cells were reported to participate in disease induction, whereas Th17 cells were increased during peak disease. There were about 10% of Th17/Th1 cells detectable at the peak of retinal inflammation [6,34,36,37]. In the chronic EAU mouse models, during the initial peak stage of inflammation, Th17 cells are more readily detected, whilst Th1 cells have limited function and only relatively few Th17/Th1 cells were observed [24].…”

Altered Metabolic Phenotype of Immune Cells in a Spontaneous Autoimmune Uveitis Model

“…To our knowledge, we are the first to describe these differences in a direct comparison between PBMC and CD4 sorted subpopulations. Since CD4 + T cells are the major players in HAU, ERU and the induced uveitis models (1,42,43), we subsequently focused on the metabolic phenotype of this specific cell subset. We could demonstrate that CD4 + T cells of ERU cases utilized the oxidative phosphorylation pathway in basal state to a significantly higher amount than control cells (Figure 1A).…”