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.