Interleukin-17 Receptor E and C-C Motif Chemokine Receptor 10 Identify Heterogeneous T Helper 17 Subsets in a Mouse Dry Eye Disease Model

Dry eye disease (DED) features the inflammatory response of the ocular surface. Pro-inflammatory T helper 17 (Th17) cells are important for the pathogenesis of DED. In the present study a mouse DED model was used to discover two Th17 subsets in draining lymph nodes and conjunctivae based on the expression of IL-17 receptor E (IL-17RE) and CCR10: IL-17RElowCCR10- Th17 and IL-17REhighCCR10+ Th17. IL-17REhighCCR10+ Th17 expressed more retinoic acid-related orphan receptor gamma t but fewer T-box-expressed-in-T-cells than IL-17RElowCCR10- Th17. In addition, the former expressed higher IL-17A, IL-21, and IL-22 but fewer IFN-γ than the latter. Further analysis showed that IL-17REhighCCR10+ Th17 did not express IFN-γ in vivo, whereas IL-17RElowCCR10- Th17 contained IFN-γ-expressing Th17/Th1 cells. Moreover, IL-17REhighCCR10+ Th17 possessed more phosphorylated p38 mitogen-activated protein kinase (MAPK) and Jnk than IL-17RElowCCR10- Th17, suggesting higher activation of MAPK signaling in IL-17REhighCCR10+ Th17. In vitro treatment with IL-17C effectively maintained IL-17A expression in Th17 cells through p38 MAPK rather than Jnk MAPK. Furthermore, the adoptive transfer of the two Th17 subpopulations indicated their equivalent pathogenicity in DED. Interestingly, IL-17REhighCCR10+ Th17 cells were able to phenotypically polarize to IL-17RElowCCR10- Th17 cells in vivo. In conclusion, the current study revealed novel Th17 subsets with differential phenotypes, functions, and signaling status in DED, thus deepening the understanding of Th17 pathogenicity, and exhibited Th17 heterogeneity in DED.