title: IL-4 attenuates pulmonary epithelial cell-mediated suppression of T cell priming.
abstract: We have previously shown that Th2-polarized airway inflammation facilitates sensitization towards new, protein antigens. In this context, we could demonstrate that IL-4 needs to act on cells of the hematopoetic and the structural compartment in order to facilitate sensitization towards new antigens. We thus aimed to elucidate possible mechanisms of action of IL-4 on structural cells choosing to analyze pulmonary epithelial cells as an important part of the lung's structural system. We used a co-culture system of DC- or APC-dependent in vitro priming of T cells, co-cultivated on a layer of cells of a murine pulmonary epithelial cell line (LA-4) pretreated with or without IL-4. Effects on T cell priming were analyzed via CFSE-dilution and flow cytometric assessment of activation status. Pulmonary epithelial cells suppressed T cell proliferation in vitro but this effect was attenuated by pre-treatment of the epithelial cells with IL-4. Transwell experiments suggest that epithelial-mediated suppression of T cell activation is mostly cell-contact dependent and leads to attenuation in an early naive T cell phenotype. Secretion of soluble factors like TARC, TSLP, GM-CSF and CCL20 by epithelial cells did not change after IL-4 treatment. However, analysis of co-stimulatory expression on pulmonary epithelial cells revealed that pre-treatment of epithelial cells with IL-4 changed expression GITR-L, suggesting a possible mechanism for the effects observed. Our studies provide new insight into the role of IL-4 during the early phases of pulmonary sensitization: The inhibitory activity of pulmonary epithelial cells in homeostasis is reversed in the presence of IL-4, which is secreted in the context of Th2-dominated allergic airway inflammation. This mechanism might serve to explain facilitated sensitization in the clinical context of polysensitization where due to a pre-existing sensitization increased levels of IL-4 in the airways might facilitate T cell priming towards new antigens.
authors.affiliation: Pediatric Pneumology, Allergology and Neonatology, Medical School Hannover, Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Albrecht
authors.forename: Markus
authors.initials: M
authors.lastname: Arnhold
authors.forename: Sandra
authors.initials: S
authors.lastname: Lingner
authors.forename: Subhashree
authors.initials: S
authors.lastname: Mahapatra
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
authors.forename: Gesine
authors.initials: G
authors.lastname: Hansen
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Dittrich
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015847:Interleukin-4 / Q000378:metabolism / Q000502:physiology*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D016212:Transforming Growth Factor beta; D015847:Interleukin-4