A2.34 Specific deletion of β-catenin signalling in dendritic cells results in lower Treg expression without influencing the severity of collagen-induced arthritis
Authors: CH Alves, JL Ober-Blöbaum, AA Brouwers-Haspels, PS Asmawidjaja, AMC Mus, BE Clausen, E Lubberts
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> 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 <i>in vivo</i> remain largely unknown. Recently, the b-catenin pathway has been suggested to promote a regulatory DC phenotype <i>in vitro</i>. 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 <i>in vitro</i> and protection from autoimmune disease in mice. The aim of this study was to unravel the <i>in vivo</i> role of β-catenin signalling to control DC function in collagen-induced arthritis (CIA). <h3>Methods</h3> 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. CIA was induced in the mutant mice and littermate controls by intra-dermal immunisation with 100 µg chicken type II collagen (CII) 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 the profiles of different T-cell and DC populations as well as their cytokine production were analysed by flow cytometry. <h3>Results</h3> Deletion of <i>β-catenin</i> in CD11c<sup>+</sup> cells had no effect on the disease course and CIA severity was not different compared to the littermate controls. Also, overexpression of <i>β-catenin</i> in CD11c<sup>+</sup> cells resulted in a similar CIA compared to littermate control mice showing no difference in onset, progression and severity of CIA. CD11c-specific deletion of <i>β-catenin</i> resulted in a decrease frequency of splenic CD3<sup>+</sup>CD8<sup>+</sup> T cells and in a decrease of Tregs (CD4<sup>+</sup>CD25<sup>+</sup>). No changes in the frequency of splenic CCR6<sup>+</sup>CXCR3<sup>-</sup>CCR4<sup>+</sup> (Th17), CCR6<sup>-</sup>CXCR3<sup>-</sup>CCR4<sup>+</sup> (Th2) and CCR6<sup>-</sup>CXCR3<sup>+</sup>CCR4<sup>-</sup>(Th1) T-cells were observed. The expression of different cytokines such as IL-10, IFNγ, IL-4, IL-17A, IL-17F and IL-22 by the CD4<sup>+</sup> T-cells was also not affected. <h3>Conclusions</h3> Our data indicate that changes in the levels of β-catenin expression in DCs did not alter the course and severity of CIA. Deletion of β-catenin results in a decrease of Tregs, however this is not sufficient to influence the onset and severity of CIA. Further characterisation of the influence of <i>β-catenin</i> on DCs and T-cell profiles needs to be performed.