Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation.
The maturation of dendritic cells (DCs) after exposure to microbial products or inflammatory mediators plays a critical role in initiating the immune response. We found that maturation can also occur under steady-state conditions, triggered by alterations in E-cadherin-mediated DC-DC adhesion. Selective disruption of these interactions induced the typical features of DC maturation including the upregulation of costimulatory molecules, MHC class II, and chemokine receptors. These events were triggered at least in part by activation of the beta-catenin pathway. However, unlike maturation induced by microbial products, E-cadherin-stimulated DCs failed to release immunostimulatory cytokines, exhibiting an entirely different transcriptional profile. As a result, E-cadherin-stimulated DCs elicited an entirely different T cell response in vivo, generating T cells with a regulatory as opposed to an effector phenotype. These DCs induced tolerance in vivo and may thus contribute to the elusive steady-state "tolerogenic DCs."
Jiang
Aimin
A
Department of Cell Biology, Ludwig Institute for Cancer Research, Yale University School of Medicine, 333 Cedar Street, PO Box 208002, New Haven, CT 06520, USA.
Bloom
Ona
O
Ono
Satoru
S
Cui
Weiguo
W
Unternaehrer
Juli
J
Jiang
Shan
S
Whitney
J Andrew
JA
Connolly
John
J
Banchereau
Jacques
J
Mellman
Ira
I
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015153:Blotting, Western; D015820:Cadherins / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D040081:Protein Array Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051820:TCF Transcription Factors / Q000276:immunology / Q000378:metabolism; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism
D015820:Cadherins; D051820:TCF Transcription Factors; D051176:beta Catenin