Abstract

Thrombospondin-1 (TSP-1) is a physiologic activator of TGF-beta, a critical induction factor for Th-17 mediated immunity. The purpose of this study was to investigate the role of TSP-1 in the induction of the Th-17 ocular surface response to desiccating stress (DS). TSP-1 knock-out (KO) and wild-type (WT) mice were subjected to DS for 5 or 10 days (DS5, DS10) and parameters of ocular surface disease including corneal barrier function, conjunctival CD4+ T cell infiltration and goblet cell (GC) density were evaluated. Desiccation increased expression of TSP-1 in conjunctival antigen presenting cells (APCs). TSP-1KO mice subjected to DS had less corneal barrier disruption, reduced loss of PAS+ GC, and decreased CD4+ T cell infiltration in the conjunctiva. In contrast to WT, TSP-1KO mice failed to upregulate MMP-3 and MMP-9 mRNA transcripts in the cornea and IL-17A mRNA transcripts in the conjunctiva. RAG-1KO recipients of adoptively transferred CD4+ T cells isolated from TSP-1KO mice subjected to DS for 5 days showed milder dry eye phenotype and less conjunctival inflammation than recipients of CD4+ T cells from DS5 WT control. Reconstitution of TSP-1KO mice with WT-APCs prior to DS reversed the resistance of the TSP-1KO to DS-induced immunopathology. In conclusion, APC-derived TSP-1 is critical for generating the Th-17 ocular surface response to DS.