Background/Purpose

Rheumatoid arthritis (RA) is an autoimmune disease characterized 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. Microbial and pro-inflammatory stimuli trigger their maturation into immunostimulatory DCs that express high levels of MHC/peptide complexes, costimulatory molecules and pro-inflammatory cytokines to induce an adaptive immune response. DCs are also important to establish self-tolerance either via the generation of regulatory T cells (Tregs) or via the induction of apoptosis or anergy of auto-reactive effector cells. However, the signaling 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 cytokines and instead drive Treg differentiation in vitroand protection from autoimmune disease in mice.

            The aim of this study was to unravel the in vivorole of β-catenin signaling to control DC function in collagen-induced arthritis (CIA).

Methods

C57BL/6 mice with a conditional deletion or activation of the β-catenin gene specifically in DCs were generated by crossing CD11c-Cre transgenic mice to β-catenin^FL/FL and β-catenin^{FL(EX3)/FL(EX3)}animals, respectively. CIA was induced in the mutant mice and littermate controls by intra-dermal immunization with 100 µg chicken type II collagen in complete Freund’s adjuvant on days 0 and 21. CIA incidence and severity was monitored macroscopically using a clinical score. On day 35, the animals were sacrificed, and spleen, draining lymph nodes, serum, ankles and knees were collected. The profiles of different T-cell and DC populations as well as their cytokine production were analyzed by flow cytometry.

Results

Deletion or overexpression of β-catenin in CD11c⁺cells did not affect the onset, progression and severity of CIA.

CD11c-specific deletion of β-catenin resulted in an increased frequency of splenic CCR6^–CXCR3⁺CD4⁺ T cells and in an increase of naturally occurring Tregs (FoxP3⁺CD25^–CD4⁺) as well as of adaptive Tregs (FoxP3⁺CD25⁺CD4⁺).

            Overexpression of β-catenin in DCs caused an increase of splenic CCR6⁺CXCR3^–CD4⁺ (Th17) and CCR6^–CXCR3⁺CD4⁺ (Th1) T-cells. The latter produced elevated levels of the Th1 cytokine IFNγ and of the immunosuppressive cytokine IL-10. We also observed an increased frequency of naturally occurring FoxP3⁺CD25^–CD4⁺ and of adaptive FoxP3⁺CD25⁺CD4⁺Tregs.

Conclusion

Our preliminary data indicate that changes in the levels of β-catenin expression in DCs did not alter the course and severity of CIA. However, the increase in IL-10 and in the Treg frequency during arthritis suggests that activation of β-catenin signaling may enhance the regulatory function of DCs.

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-beta-catenin-signaling-to-control-dendritic-cell-function-in-collagen-induced-arthritis/