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 for long time periods at an immature stage in epithelia before migrating to T-cell-rich areas of regional lymph nodes to become mature interdigitating dendritic cells (DCs). LCs express the epithelial adhesion molecule E-cadherin and undergo homophilic E-cadherin adhesion with surrounding epithelial cells. Using a defined serum-free differentiation model of human CD34(+) hematopoietic progenitor cells, it was demonstrated that LCs generated in vitro in the presence of transforming growth factor beta1 (TGF-beta1) express high levels of E-cadherin and form large homotypic cell clusters. Homotypic LC clustering can be inhibited by the addition of anti-E- cadherin monoclonal antibodies (mAbs). Loss of E-cadherin adhesion of LCs by mechanical cluster disaggregation correlates with the rapid up-regulation of CD86, neo-expression of CD83, and diminished CD1a cell surface expression by LCs-specific phenotypic features of mature DCs. Antibody ligation of E-cadherin on the surfaces 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 inhibits the acquisition of mature DC features. E-cadherin-mediated LC maturation suppression may represent a constitutive active epithelial mechanism that prevents the uncontrolled maturation of immature LCs. (Blood. 2000;96:4276-4284)
Riedl
E
E
Vienna International Research Cooperation Center/Novartis Research Institute, Austria. elisabeth.riedl@univie.ac.at
Stöckl
J
J
Majdic
O
O
Scheinecker
C
C
Knapp
W
W
Strobl
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D018949:Antigens, CD1 / Q000096:biosynthesis; D051940:B7-2 Antigen; D023201:CD40 Ligand / Q000502:physiology; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002449:Cell Aggregation; D002454:Cell Differentiation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D005312:Fetal Blood / Q000166:cytology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007136:Immunoglobulins / Q000096:biosynthesis; D007801:Langerhans Cells / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D019089:Stem Cell Factor / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097802:CD83 Antigen
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018949:Antigens, CD1; D051940:B7-2 Antigen; D023201:CD40 Ligand; D015820:Cadherins; D015815:Cell Adhesion Molecules; D016895:Culture Media, Serum-Free; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007136:Immunoglobulins; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C497965:Cd86 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C084881:flt3 ligand protein