Besides their well-characterized role as initiators of adaptive immune responses, dendritic cells (DCs) also play a critical role in the induction and maintenance of tolerance. A failure of the first role will produce immunodeficiency, while the failure of a key function in tolerance leading to autoimmune and/or inflammatory diseases. Although it is clear that tolerance is a property of DCs at the steady state, the molecular mechanisms governing their generation, regulation and function remain poorly understood. Our recent studies have uncovered the E-cadherin/b-catenin signaling pathway as a novel maturation pathway that achieves DC maturation without inflammatory cytokines. Best studied in epithelial cells, E-cadherin forms a complex with members of the catenin family, which control interactions with the actin cytoskeleton and (after translocation to the nucleus) act as cofactors for T cell factor (TCF; and lymphoid enhancing factor, LEF) transcriptional activators. Under resting conditions, the bulk of b-catenin is sequestered to the E-cadherin cytoplasmic domain, with the cytosolic pool further attenuated by its phosphorylation by glycogen synthase kinase-3b (GSK-3b and subsequent proteasomal degradation. Activation of Wnt signaling activates TCF dependent transcription by increasing free b-catenin due in part to an inhibition of GSK-3b.
Further studies showed that 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 vivoand more importantly, immunization with these DCs provided complete protection against autoimmune diseases in Experimental Autoimmune Encephalomyelitis (EAE). Interestingly, while DCs matured upon disruption of E-cadherin-mediated clusters were functional tolerogenic, upon further TLR ligation they displayed a strong Th1 cytokine profile and much enhanced antigen presentation capacity consistent with enhanced immunity. Thus E-cadherin/b-catenin signaling might serve as a novel signal that contributes to the elusive steady state “tolerogenic DCs”.
While our findings strongly suggested a role of E-cadherin/b-catenin signaling in regulating DC maturation and function in both cultured murine and human DCs, it remains an open question whether E-cadherin/b-catenin signaling functions similarly under physiological conditions. The embryo lethality of mice deficient in E-cadherin and b-catenin, however, presents a major hurdle to directly address this question. Recognizing this challenge, we have generated a series of CD11c-specific conditional knockout mice mice that either inactivate b-catenin signaling by deletion (b-catenin-/- and E-cadherin-/-) or activate the pathway by making b-catenin constitutively active (b-catenin Exon3-/-), in collaboration with Bjoern Clausen in Amsterdam. These mice will allow me to directly address the role of E-cadherin/b-catenin signaling in a variety of settings. Our preliminary results showed a time-dependent increase in percentage of spontaneously mature DCs with constitutively active â-catenin than that of wild type DCs (Figure 2A), consistent with activation of b-catenin as a tolerizing signal for DCs. Not surprisingly, DCs with constitutively active â-catenin exhibited diminished IL-12p40 response, with only 12.8% became IL-12p40 producing cells compared to 27% for wild type DCs (Figure 2B left panels). Further, consistent with our previous results, CD failed to induce IL-12p40 production from wild type and mutant DCs (Figure 2B right panels). Current efforts are made to confirm the role of E-cadherin/b-catenin signaling in mediating DC tolerance, especially under autoimmune disease settings.
Due to their pivotal role in controlling both immune and tolerance responses, DCs have emerged as good candidates to modulate the immune system in an antigen-specific manner with immunotherapy for both cancers and autoimmune/inflammatory diseases. However, the underlying mechanisms for the regulation of DC function, especially tolerance, remained poorly understood, critically hindering successful application of these approaches. Our studies suggested E-cadherin/b-catenin signaling pathway as a novel mechanism to generate tolerogenic DCs, and showed that these tolerogenic DCs could be converted into highly immunogenic DCs upon certain treatments. Thus, a therapeutic strategy that enhances the tolerance or immunity function of DCs by targeting E-cadherin/b-catenin signaling pathway may represent an attractive approach for treatment of autoimmune/allergic diseases and cancer, respectively. We are currently focusing on (1) Investigate the role of E-cadherin/â-catenin signaling pathway in modulating DC function in preclinical animal models for autoimmune and allergic diseases including multiple sclerosis (MS) and asthma, and examine therapeutic effects of activating the E-cadherin/b-catenin signaling pathway in DCs with preclinical animal models to enhance antigen-specific tolerance for immunotherapy (See Figure 3 for a model for EAE). (2) Explore new strategy targeting â-catenin signaling pathway to enhance anti-tumor immunity for cancer immunotherapy. As E-cadherin/b-catenin functions similarly in human CD34+-derived DCs widely used in immunotherapy trials, and great efforts have already being made to develop specific GSK-3 and b-catenin inhibitors for drug development, our research could have immediate clinical impact.
Lab Member - Chunmei Fu, Research Associate
After getting my M.S. in Toxicology at the University of Washington, I worked as a research associate with Dr. Karen Reinisch at Yale. I joined the Jiang lab in 2008.