IL-33-Driven ILC2 Activation Maintains Ocular Surface Immune Homeostasis in Dry Eye.

PURPOSE: Although the ocular surface employs intrinsic mechanisms to counteract environmental stress, the endogenous circuits enforcing resilience against the inflammatory cycle of dry eye disease (DED) remain undefined. This study aimed to identify the cellular effectors and molecular mechanisms driving this exposure-responsive repair program. METHODS: A prospective self-controlled cohort of 30 healthy adults undergoing prolonged visual display terminal (VDT) use and a murine desiccating stress model were utilized. Ocular surface alterations were clinically assessed. Cellular and molecular responses were characterized using bulk RNA sequencing, single-cell transcriptomic profiling, flow cytometry, and functional manipulation in wild-type and genetically modified mice, including Il33-/- and Rag2-/-γc-/- mice. RESULTS: Ocular surface pathology exhibited a biphasic response, with initial deterioration followed by spontaneous partial recovery synchronized with goblet cell and MUC5AC rebound. Single-cell analysis identified conjunctival group 2 innate lymphoid cells (ILC2s)-not adaptive Th2 cells-as the predominant stress-responsive source of the goblet-cell trophic factor IL-13. Conjunctival ILC2s exhibited a unique tissue-resident, ST2-high, and secretion-biased phenotype distinct from their intestinal counterparts. Mechanistically, epithelial-derived IL-33 drove this protective response. Exogenous IL-33 expanded resident ILC2s and accelerated barrier recovery, whereas genetic deletion of Il33 or deficiency of the γc-dependent lymphoid compartment was associated with impaired repair responses and exacerbated disease severity. CONCLUSIONS: The IL-33/ST2-ILC2 axis, with coordinated IL-13 and AREG outputs, constitutes a critical innate repair module that promotes mucosal healing under desiccating stress. These findings provide mechanistic insights into ocular surface resilience, and a framework for investigating endogenous repair in early-stage or environmentally induced DED.