Inhaled peptide challenge has been shown to induce T cell‐mediated, isolated late asthmatic reaction (
LAR), characterized by recruitment of CD4+ Tcells 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
Tcell‐induced LARand recruitment of CD4+ Tcells by examining the effects of Tcell‐derived factors on the induction of TSLPin primary bronchial epithelial cells ( PBEC). Methods PBECgrown 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 Tcells. TSLPwas measured in PBECculture 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 TSLPwas measured using a bioassay involving the induction of CCL17 production from monocyte‐derived dendritic cells (mo DC). Results
RNAand allergen‐specific T cells induced enhanced TSLPsecretion from asthmatic PBECcompared to healthy PBEC. Activated PBECculture supernatant induced TSLP‐dependent CCL17 production from mo DCin 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
TSLPproduction by epithelial cells, suggesting T cell–airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLPis currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLPexpression ( Tcell‐derived factors) may be equally relevant in the treatment of allergic inflammation.