Dataset Information

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

ABSTRACT: 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 ?-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of ?-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of ?-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 these cells in response to a TLR2 or TLR4 ligand stimulation. CIA was induced by intra-dermal immunization with 100 ?g chicken type II collagen in complete Freund's adjuvant on days 0 and 21. CIA incidence and severity was monitored macroscopically and by histology. The T cell profile as well as their cytokine production were analysed by flow cytometry. Lack of ?-catenin specifically in DCs did not affect the spontaneous, TLR2- or TLR4-induced maturation and activation of BMDCs or their cytokine production. Moreover, no effect on the incidence and severity of CIA was observed in mice lacking ?-catenin in CD11c+ cells. A decreased frequency of splenic CD3+CD8+ T cells and of regulatory T cells (Tregs) (CD4+CD25highFoxP3+), but no changes in the frequency of splenic Th17 (CCR6+CXCR3-CCR4+), Th2 (CCR6-CXCR3-CCR4+) and Th1 (CCR6-CXCR3+CCR4-) cells were observed in these mice under CIA condition. Furthermore, the expression of IL-17A, IL-17F, IL-22, IL-4 or IFN? was also not affected. Our data indicate that ablation of ?-catenin expression in DCs did not alter the course and severity of CIA. We conclude that although deletion of ?-catenin resulted in a lower frequency of Tregs, this decrease was not sufficient to aggravate the onset and severity of CIA.

SUBMITTER: Alves CH

PROVIDER: S-EPMC4654567 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Alves C Henrique CH Ober-Blöbaum Julia L JL Brouwers-Haspels Inge I Asmawidjaja Patrick S PS Mus Adriana M C AM Razawy Wida W Molendijk Marlieke M Clausen Björn E BE Lubberts Erik E

PloS one 20151120 11

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 β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically ...[more]

PMID: 26587585

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Project description:Regulatory T (Treg) cells have anti-inflammatory functions and heighten immune tolerance. The proportion and functions of Treg cells are perturbed in rheumatoid arthritis (RA), contributing to the excessive immune activation associated with this disease. We therefore hypothesized that supplementation with foreign Treg cells could be used to treat RA. To investigate the therapeutic effects of exogenous Treg cells on RA and its mechanism, we used human Treg cells to treat collagen-induced arthritis (CIA) in a rat model to observe whether exogenous Treg cells can treat the disease across species. Successful treatment would indicate that Treg cell transplantation in humans is more likely to affect RA. In the present study, human Treg cells were collected from healthy human peripheral blood and culture-expanded in vitro. Induced human Treg cells were injected into CIA rats via the tail vein. The rats' lymphocyte subtypes, cytokines, and Th1/Th2 ratios were measured using flow cytometry. In the rats, following injection of the human Treg cells, the severity of CIA was significantly reduced (P < 0.01), the proportion of endogenous Treg cells increased in the peripheral blood and spleen (P = 0.007 and P < 0.01, respectively), and the proportion of B cells decreased (P = 0.031). The IL-5 level, IL-6 level, and Th1/Th2 ratio in the peripheral blood were decreased (P = 0.013, 0.009, and 0.012, respectively). The culture-expanded human Treg cells were also cultured with synovial fibroblast cells from RA patients (RASFs). After coculture with Treg cells, RASFs showed reduced proliferation (P < 0.01) and increased apoptosis (P = 0.037). These results suggest that exogenous and induced Treg cells can produce a therapeutic effect in RA and CIA by increasing endogenous Treg cells and RASF apoptosis and reducing B cells, the Th1/Th2 ratio, and secretion levels of IL-5 and IL-6. Treg cell transplantation could serve as a therapy for RA that does not cause immune rejection.

Project description:Rheumatoid arthritis (RA) is an autoimmune disease that affects ~1% of the world's population. B cells and autoantibodies play an important role in the pathogenesis of RA. The P2RX7 receptor is an ATP-gated cation channel and its activation results in the release of pro-inflammatory molecules. Thus, antagonists of P2RX7 have been considered to have potential as novel anti-inflammatory therapies. Although originally identified for its role in innate immunity, P2RX7 has recently been found to negatively control Peyer's patches (PP) T follicular helper cells (Tfh), which specialize in helping B cells, under homeostatic conditions. We have previously demonstrated that PP Tfh cells are required for the augmentation of autoimmune arthritis mediated by gut commensal segmented filamentous bacteria (SFB). Thus, we hypothesized that P2RX7 is required to control autoimmune disease by keeping the Tfh cell response in check. To test our hypothesis, we analyzed the impact of P2RX7 deficiency in vivo using both the original K/BxN autoimmune arthritis model and T cell transfers in the K/BxN system. We also examined the impact of P2RX7 ablation on autoimmune development in the presence of the gut microbiota SFB. Our data illustrate that contrary to exerting an anti-inflammatory effect, P2RX7 deficiency actually enhances autoimmune arthritis. Interestingly, SFB colonization can negate the difference in disease severity between WT and P2RX7-deficient mice. We further demonstrated that P2RX7 ablation in the absence of SFB caused reduced apoptotic Tfh cells and enhanced the Tfh response, leading to an increase in autoantibody production. It has been shown that activation of TIGIT, a well-known T cell exhaustion marker, up-regulates anti-apoptotic molecules and promotes T cell survival. We demonstrated that the reduced apoptotic phenotype of P2rx7 -/- Tfh cells is associated with their increased expression of TIGIT. This suggested that while P2RX7 was regulating the Tfh population by promoting cell death, TIGIT may have been opposing P2RX7 by inhibiting cell death. Together, these results demonstrated that systemic administration of general P2RX7 antagonists may have detrimental effects in autoimmune therapies, especially in Tfh cell-dependent autoimmune diseases, and cell-specific targeting of P2RX7 should be considered in order to achieve efficacy for P2RX7-related therapy.

Project description:ObjectiveDendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3? regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGF?-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2?/?) mice had impaired DCs migration and reduced CD8?? DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2?/? mice, we tested the hypothesis that CD8?? DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8?? DCs in Ccr2?/? and SKG mice.MethodsTo examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8?? DCs.ResultsFlt3L-mediated expansion of endogenous CD8?? DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8?? DCs ameliorated arthritis in Ccr2?/? mice and enhanced TGF?1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype.ConclusionCD8?? DCs were tolerogenic to the development of arthritis. CD8?? DCs deficiency heightened the sensitivity to arthritis in Ccr2?/? mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2?/? mice was T cell-independent.

Dataset Information

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

Publications

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

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