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Yihe Chen, Sunil K Chauhan, Zahra Sadrai, Jing Hua, Masahiro Omoto, Reza Dana; Th17-derived IFN-γ+IL-17+ effectors exacerbate dry eye disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4604.
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Th17 cells have been shown to play a critical role in the induction and maintenance of dry eye disease (DED). In this study, we investigated whether Th17 cells can further differentiate into IL-17+IFN-γ+ (Th17/1) cells in DED. In addition, the functionality of these double positive Th17/1 cells in DED was examined.
DED was induced in wild-type (WT) B6 mice using the controlled environmental chamber (CEC) for 14 days. The draining lymph nodes (DLN) of DED mice were harvested, and Th17 (IL-17+IFN-γ-), Th17/1 (IL-17+IFN-γ+), and Th1 (IL-17-IFN-γ+) subsets were sorted using cytokine secretion assay kits. Each of these subsets was subsequently injected intravenously into naïve B6 Rag-/- mice, which were then placed in the CEC for 5 days. Disease severity was evaluated using corneal fluorescein staining (CFS). T cell cytokine secretion was analyzed using flow cytometry. Chronic DED was developed by placing WT B6 mice in the CEC for 14 days and then housing them in a standard environment for additional 3 months. Thereafter, chronic DED mice were re-challenged using the CEC for 7 days. Disease severity and T cell response were evaluated using the same methods as described above.
Upon adoptive T cell transfer into Rag-/- mice, Th17 and Th17/1 recipients showed similar disease onset and severity of DED identified by significant punctate corneal staining with a score of 10/15 and 8/15, respectively. Mice receiving Th1 cells only exhibited mild severity (CFS score 4/15). After transfer, 15% of the purified Th17 cells converted to IFN-γ/IL-17-double positive cells in the DLNs. 20% of the transferred Th17/1 cells became IFN-γ single-positive cells, and 13% of them differentiated to IL-17 single-positive cells. On the conjunctivae from mice receiving Th17 or Th17/1 cells, we found 10% IL-17+IFN-γ+ cells in each group. Mice with chronic DED showed a dramatic exacerbation of the disease, along with a rapid generation of Th17/1 as early as day 7 at both the DLNs and conjunctivae.
These data demonstrate that in DED Th17/1 cells are derived from Th17 precursors, and that ‘double-positive’ cells are critical effectors in exacerbating the disease. Further elucidation of the cytokine microenvironment determining the differentiation of Th17/1 cells is needed for the development of more effective immunomodulatory strategies in DED therapy.
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