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 TH 2 responses via CCL17 production.


OBJECTIVE
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 (dsRNA) 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 (moDC).


RESULTS
Both dsRNA 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 moDC in a manner related to clinical asthmatic status. IL-1β, IL-6, and CXCL8, rather than TH 2 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.


CONCLUSIONS
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.
Division of Allergy & Clinical Immunology, Department of Medicine, McMaster University, Hamilton, ON, Canada.
C C K
CC
Hui
D M
DM
Murphy
H
H
Neighbour
M
M
Al-Sayegh
S
S
O'Byrne
B
B
Thong
J A
JA
Denburg
M
M
Larché
D000328:Adult; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D001980:Bronchi / Q000276:immunology / Q000378:metabolism; D002415:Cats; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D055815:Young Adult; D000094632:Thymic Stromal Lymphopoietin
D000485:Allergens; D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D016328:NF-kappa B; D051196:Toll-Like Receptor 3; D007073:Immunoglobulin E; D011070:Poly I-C; D000094632:Thymic Stromal Lymphopoietin
CCL17; T cells; TSLP; airway epithelial cells; allergens; asthma; dendritic cells