Lymphotoxin β receptor signaling induces the chemokine CCL20 in intestinal epithelium

Abstract

Background & Aims: The follicle-associated epithelium (FAE) that overlies Peyer's patches (PPs) exhibits distinct features compared with the adjacent villus epithelium. Besides the presence of antigen-sampling membranous M cells and the down-regulation of digestive functions, it constitutively expresses the chemokine CCL20. The mechanisms that induce FAE differentiation and CCL20 expression are poorly understood. The aim of this work was to test whether lymphotoxin β receptor signaling (LTβR), which plays a central role in PPs' organogenesis, mediates CCL20 gene expression in intestinal epithelial cells. Methods: CCL20, lymphotoxin β (LTβ) and LTβR expression were monitored during embryonic development by in situ hybridization of mouse intestine. The human intestinal epithelial cell line T84 was used to study CCL20 expression following LTα1/β2 stimulation. In vivo CCL20 expression following agonistic anti-LTβR antibody treatment was studied by laser microdissection and quantitative RT-PCR. Results: CCL20 was expressed in the FAE before birth at the time when the first hematopoietic CD4+CD3- appeared in the PP anlage. LTβR was expressed in the epithelium during PP organogenesis, making it a putative target for LTα1β2signals. In vitro, CCL20 was induced in T84 cells upon LTβR signaling, either using an agonistic ligand or anti-LTβ receptor agonistic antibody. LTα1β2-induced CCL20 expression was found to be NF-κB dependent. LTβR signaling up-regulated CCL20 expression in the small intestinal epithelium in vivo. Conclusions: Our results show that LTβR signaling induces CCL20 expression in intestinal epithelial cells, suggesting that this pathway triggers constitutive production of CCL20 in the FAE.