Abstract
Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (Spdef) knockout mice (Spdef−/−) that lack GCs and are a novel model of dry eye. Stimulated GC degranulation increased antigen binding to GC mucins. Induction of tolerance to topically applied OVA measured by cutaneous delayed type hypersensitivity (DTH) was observed in WT, but not Spdef−/−. OTII CD4+ T cells primed by dendritic cells (DCs) from the conjunctival draining lymph nodes of Spdef−/− had greater IFN-γ production and lower Foxp3 positivity than those primed by WT DCs. These findings indicate that conjunctival GCs contribute to ocular surface immune tolerance by modulating antigen distribution and antigen specific immune response. GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye.
Highlights
Gel-forming mucins secreted by goblet cells (GCs), through their ability to retain water, can form a highly hydrated mucus gel that covers and protects mucosal surfaces [1]
The least epithelial retention was noted for OVA peptide, and the greatest stromal localization was noted for the two smallest sized antigens, 2.3 kDa OVA peptide and 10 kDa dextran which migrated in columnar or oval patterns
Ovalbumin (OVA, 45 kDa), the antigen used in our immune tolerance assays passed into the stroma in wild type C57BL/6 (WT), but it was retained within the epithelium in the SAM pointed domain containing ETS transcription factor (Spdef) −/− (Figure 1B)
Summary
Gel-forming mucins secreted by goblet cells (GCs), through their ability to retain water, can form a highly hydrated mucus gel that covers and protects mucosal surfaces [1]. GC loss is associated with greater ocular surface epithelial disease and higher expression of the Th1 cytokine IFN-γ in aqueous deficient dry eye and mouse models of dry eye, suggesting that conjunctival GC mucins have an immunomodulatory function [5,6,7]. Goblet cell associated passages (GAPs) under cholinergic regulation have been described in the mouse small intestine [10,11] These GAPs deliver luminal antigens to a subset of dendritic cells (DCs) in the underlying lamina propria that are known to promote immune tolerance [10]. This study explored the function of GCs in distribution of topically applied antigen and induction of tolerance to antigens applied to the ocular surface of wild type and Spdef −/− mice
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