T cell-mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells.

Background Inhaled peptide challenge has been shown to induce T cell-mediated, isolated late asthmatic reaction ( LAR), characterized by recruitment of CD4+ T cells and increased levels of thymus and activation-regulated chemokine ( TARC; CCL17). Epithelial-derived thymic stromal lymphopoietin ( TSLP) has been shown to modulate dendritic cell function to promote TH2 responses via CCL17 production. Objectives To elucidate the mechanisms involved in allergen-specific T cell-induced LAR and recruitment of CD4+ T cells by examining the effects of T cell-derived factors on the induction of TSLP in primary bronchial epithelial cells ( PBEC). Methods PBEC grown at air-liquid interface from healthy individuals and patients with asthma were stimulated with double-stranded RNA (ds RNA) or supernatants from activated allergen-specific T cells. TSLP was measured in PBEC culture supernatants. Neutralizing antibodies and signalling inhibitors were used to examine the mechanisms responsible for the induction of epithelial-derived TSLP. The functional activity of PBEC-derived TSLP was measured using a bioassay involving the induction of CCL17 production from monocyte-derived dendritic cells (mo DC). Results Both ds RNA and allergen-specific T cells induced enhanced TSLP secretion from asthmatic PBEC compared to healthy PBEC. Activated PBEC culture supernatant induced TSLP-dependent CCL17 production from mo DC in a manner related to clinical asthmatic status. IL-1β, IL-6, and CXCL8, rather than TH2 cytokines ( IL-4/5/13), appeared to be the principle mediators of allergen-specific T cell-dependent induction of epithelial-derived TSLP, which was regulated by the MEK, MAPK, and NFκB pathways. Conclusion and Clinical Relevance Our data reveal a novel effect of allergen-specific T cells as a positive regulator of TSLP production by epithelial cells, suggesting T cell-airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLP is currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLP expression ( T cell-derived factors) may be equally relevant in the treatment of allergic inflammation. [ABSTRACT FROM AUTHOR]