Ligation of E-cadherin on in vitro-generated immature Langerhans-type dendritic cells inhibits their maturation

Epithelial tissues of various organs contain immature Langerhans cell (LC)- type dendritic cells, which play key roles in immunity. LCs reside far long time periods at an immature stage in epithelia before migrating to T-cell- rich areas of regional lymph nodes to become mature interdigitating dendrit ic cells (DCs). LCs express the epithelial adhesion molecule E-cadherin and undergo hemophilic E-cadherin adhesion with surrounding epithelial cells, Using a defined serum-free differentiation model of human CD34(+) hematopoi etic progenitor cells, it was demonstrated that LCs generated in vitro in t he presence of transforming growth factor beta1 (TGF-beta1) express high le vels of E-cadherin and form large homotypic cell clusters, Homotypic LC clu stering can be inhibited by the addition of anti-E-cadherin monoclonal anti bodies (mAbs). Loss of E-cadherin adhesion of LCs by mechanical cluster dis aggregation correlates with the rapid up regulation of CD86, neo-expression of CD83, and diminished CD1a cell surface expression by LCs-specific pheno typic features of mature DCs. Antibody ligation of E-cadherin on the surfac es of immature LCs after mechanical cluster disruption strongly reduces the percentages of mature DCs. The addition of mAbs to the adhesion molecules LFA-1 or CD31 to parallel cultures similarly inhibits homotypic LC cluster formation, but, in contrast to anti-E-cadherin, these mAbs fail to inhibit DC maturation. Thus, E-cadherin engagement on immature LCs specifically inh ibits the acquisition of mature DC features. E-cadherin-mediated LC maturat ion suppression may represent a constitutive active epithelial mechanism th at prevents the uncontrolled maturation of immature LCs. (C) 2000 by The Am erican Society of Hematology.