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Yihe Chen, Sunil Chauhan, Zahra Sadrai, Jing Hua, Reza Dana; What Is the Lineage of IL-17+IFN-γ+CD4+ T Cells in Dry Eye Disease?. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2038.
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IL-17-producing CD4+ T cells (Th17 cells) have been implicated in the pathogenesis of dry eye disease (DED). However, recent findings have revealed that Th17 cells represent a less-differentiated subset capable of long-term persistence and developmental plasticity, including conversion to an IFN-γ-expressing subset. In this study, we examined the IL-17+IFN-γ+CD4+ T cells that emerge in DED, and characterized their lineage.
DED was induced by housing C57BL/6 mice in a controlled environmental chamber (CEC) for 14 days (no scopolamine was administered). The conjunctivae and draining lymph nodes (DLN) were harvested at days 0, 7, and 14 for flow cytometry of three CD4+ subsets: IL-17+IFN-γ- (Th17), IL-17-IFN-γ+ (Th1), and IL-17+IFN-γ+ (Th17/1). These subsets were further characterized for Th1 and Th17 lineage-associated receptors IL-12Rβ2 and IL-23R, as well as transcription factors T-bet and RORγ(t).
There was a gradual increase in the frequencies of Th17 and Th17/1, but not Th1, subsets in both the DLN and conjunctivae over the 14 days of DED induction. Th17 subset in the DLN and conjunctivae exhibited a significant increase at both day 7 (p = 0.03 in the DLN and 0.04 in the conjunctivae) and day 14 (p = 0.03 in the DLN and 0.02 in the conjunctivae) as compared to day 0. However, Th17/1 subset showed a significant increase only at day 14 from day 0 in the DLN (0.14±0.01% vs. 0.05±0.01%, p = 0.01), and in the conjunctivae (1.6±0.3% vs. 0.2±0.1%, p = 0.04). The percentages of IL-12Rβ2- and IL-23R-expressing Th17/1 subsets in the DLN were 30% and 27%, respectively, and in the conjunctivae were 9% and 92%, respectively. The expression level of IL-12Rβ2 on Th17/1, as measured by mean fluorescein intensity (MFI), was lower in the conjunctivae (MFI=1255) than in the DLN (MFI=2595), however, the level of IL-23R on Th17/1 was higher in the conjunctivae (MFI=1921) than in the DLN (MFI=837). In addition, Th17/1 in DED conjunctivae showed a predominant expression of RORγ(t) over T-bet (the ratio of RORγ(t)/T-bet intensity was 7).
These data demonstrate that Th17/1 subset emerges subsequent to Th17 subset in DED. On the ocular surface this Th17/1 subset is predominantly of a Th17 lineage, suggesting that the inflamed eye drives the conversion of ‘plastic’ Th17 cells into cells that co-express IFN-γ.
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