Dendritic Cell-Specific Deletion of β-Catenin Results in Fewer Regulatory T-Cells without Exacerbating Autoimmune Collagen-Induced Arthritis.

Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The beta-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of beta-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of beta-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgenic mouse line. Bone marrow-derived DCs (BMDCs) were generated and used to study the maturation profile of …

Beta-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8(+) T cells

Tumors activate -catenin in DCs to suppress CD8 immunity by inhibiting cross-priming; -catenin-suppressed CD8 immunity could be rescued by enhancing cross-priming. Whereas CD8(+) T cells are essential for anti-tumor immunity, tumors often evade CD8(+) T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8(+) T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8(+) T ce…

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10

Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how β-catenin exerts its functions remains incompletely understood. Here we report that activation of β-catenin in DCs inhibits cross-priming of CD8(+) T cells by up-regulating mTOR-dependent IL-10, suggesting blocking β-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-β-catenin(-/-) (CD11c-specific deletion of β-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-β-catenin(-/-) mice were deficient in generating CD8(+) T-cell immunit…

A2.34 Specific deletion of β-catenin signalling in dendritic cells results in lower Treg expression without influencing the severity of collagen-induced arthritis

Background and objectives Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation and synovial infiltration of immune cells. T-cell priming by activated dendritic cells (DCs) contributes to the pathogenesis of RA. DCs are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating the tolerogenic DC function in vivo remain largely unknown. Recently, the b-catenin pathway has been suggested to promote a regulatory DC phenotype in vitro . While activation of β-catenin causes the phenotypic maturation of bone marrow-derived DCs, these cells fail to produce immunogenic …

Aldara-Induced Psoriasis-Like Skin Inflammation: Isolation and Characterization of Cutaneous Dendritic Cells and Innate Lymphocytes

Psoriasis is a chronic auto-inflammatory skin disease of unknown etiology affecting millions of people worldwide. Dissecting the cellular networks and molecular signals promoting the development of psoriasis critically depends on appropriate animal models. Topical application of Aldara cream containing the Toll-like receptor (TLR)7-ligand Imiquimod induces skin inflammation and pathology in mice closely resembling plaque-type psoriasis in humans. The particular power of the Aldara model lies in examining the early events during psoriatic plaque formation, which is difficult to achieve in patients. Hence, recent reports using this model have challenged currently prevailing concepts concernin…

Langerinneg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice.

Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective ac…

IL-10 signaling in dendritic cells attenuates anti- Leishmania major immunity without affecting protective memory responses

Monitoring Skin Dendritic Cells in Steady State and Inflammation by Immunofluorescence Microscopy and Flow Cytometry

Skin dendritic cells (DC) are strategically positioned at the body's second largest epithelial border to the environment. Hence they are the first antigen presenting cells that encounter invading pathogens and environmental antigens, including contact sensitizers and carcinogens penetrating the skin. Moreover, DC have the unique ability to induce immunity or tolerance and thus take center stage in regulating innate and adaptive immune responses. Skin DC can be divided into several phenotypically and functionally distinct subtypes. The three main subsets are Langerin+ epidermal Langerhans cells (LC) and Langerin+ as well as Langerinneg dermal DC. In the steady state skin DC form a dense netw…