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-17RECCR10 Th17 and IL-17RECCR10 Th17. IL-17RECCR10 Th17 expressed more retinoic acid-related orphan receptor gamma t but fewer T-box-expressed-in-T-cells than IL-17RECCR10 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-17RECCR10 Th17 did not express IFN-γ in vivo, whereas IL-17RECCR10 Th17 contained IFN-γ-expressing Th17/Th1 cells. Moreover, IL-17RECCR10 Th17 possessed more phosphorylated p38 mitogen-activated protein kinase (MAPK) and Jnk than IL-17RECCR10 Th17, suggesting higher activation of MAPK signaling in IL-17RECCR10 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-17RECCR10 Th17 cells were able to phenotypically polarize to IL-17RECCR10 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.