Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells

Kim, Yong‐Gil; Lee, Chang‐Keun; Nah, Seong‐Su; Mun, Se Hwan; Yoo, Bin; Moon, Hee‐Bom

doi:10.1016/j.bbrc.2007.04.042

Cited by 147 publications

(107 citation statements)

References 26 publications

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“…The increase in systemic bone mass observed in WT and hTNFtg mice treated with CD28 SA was consistent with the observed decrease in serum levels of markers for bone destruction and unchanged serum markers of bone-formation markers. This hypothesis is reinforced by recent studies showing that Treg cells can directly block osteoclast differentiation in vitro (24,39,40). Interestingly, it was demonstrated that the defects in Treg cell function in RA patients resulted from defects in CTLA-4 surface expression (41).…”

Section: Discussionmentioning

confidence: 91%

Regulatory T Cells Protect from Local and Systemic Bone Destruction in Arthritis

Zaiss¹,

Frey²,

Heß

et al. 2010

The Journal of Immunology

178

132

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We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-α–induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-κB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 91%

Regulatory T Cells Protect from Local and Systemic Bone Destruction in Arthritis

Zaiss¹,

Frey²,

Heß

et al. 2010

The Journal of Immunology

178

132

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“…Indeed, Treg cells are known to control the proliferation of activated T cells (21,35). Treg cells have also been shown to directly regulate B cells in animal models as well as in humans, and blockage of CD4ϩCD25ϩ B cell regulation leads to the production of autoantibodies (36,37). In addition, the close correlation between an increase in Treg cells and clearance of HCV in our MC patients underscores the role of HCV as a trigger in MC vasculitis.…”

mentioning

confidence: 73%

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

Landau¹,

Rosenzwajg²,

Saadoun³

et al. 2008

Arthritis & Rheumatism

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Objective. Mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells. The aim of this study was to prospectively evaluate the evolution of this defect during the course of antiviral treatment.Methods. Treg cell frequencies and numbers were analyzed in 131 patients with chronic HCV infection (including 66 with MC vasculitis) and 20 healthy volunteer donors. Measurements were taken before, during, and after treatment with PEGylated interferon alfa-2b plus ribavirin.Results. At baseline, patients with MC vasculitis had a significantly lower frequency and number of Treg cells than did patients without MC vasculitis. Complete remission of MC vasculitis following antiviral treatment was associated with a significant increase in Treg cell levels compared with baseline. In contrast, Treg cell levels in nonresponders or partial responders, which did not differ from those in complete responders at baseline, remained unchanged over the course of the study. Conclusion. The strong positive correlation between clinical responses and Treg cell levels provides further support for the central role of Treg cells in the pathogenesis of HCV-induced MC vasculitis and emphasizes the dual role of Treg cells in chronic HCV infection: while Treg cells may hinder viral elimination, they also limit autoimmune injury.Chronic infection with hepatitis C virus (HCV) is the main cause of mixed cryoglobulinemia (MC) vasculitis, a potentially life-threatening systemic vasculitis (1). MC is a B cell proliferative disorder characterized by polyclonal or monoclonal activation and autoantibody production. MC may lead to clinical manifestations ranging from an MC syndrome (purpura, arthralgia, asthenia) to a more serious vasculitis with nervous system and renal involvement (1). The observation of T cells in the vascular infiltrates and the presence of autoantibodies, together with the observation that some HLA groups confer susceptibility to MC vasculitis in HCV-infected patients, suggest that autoimmune processes are implied in this virus-induced disease (2,3). It has been demonstrated that antiviral treatment can lead to the disappearance of symptoms and can induce an immunologic response, i.e., a significant decrease in plasma cryoglobulin levels (4). Furthermore, the clinical response is closely related to effective viral elimination (4,5), supporting the causal link between chronic HCV infection and the autoimmune process.During the past several years, CD4ϩCD25 high immunoregulatory T cells have been identified in

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“…Kim et al found that Treg cells inhibit osteoclast differentiation from peripheral blood mononuclear cells (PBMCs) in a cytokine-dependent and cell-to-cell contact-independent manner and proposed that TGF-b and IL-4 may be the key cytokines for the suppressive function of Treg cells. 14 Zaiss et al concluded that Treg cells suppress osteoclast formation primarily through cell-to-cell contact via cytotoxic T lymphocyte antigen 4(CTLA-4), suggesting that IL-4 and IL-10 contributed to, but were not necessary for, the inhibitory effect. 15 The goal of the present study was to elucidate the mechanisms underlying the modulation of OC differentiation and bone resorption by Treg cells, and to investigate the role of 17b-estradiol (E2) in this process.…”

Section: Introductionmentioning

confidence: 99%

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

et al. 2010

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Cross-talk has been shown to occur between the immune system and bone metabolism pathways. In the present study, we investigated the impact of CD4 1 CD25 1 Foxp3 1 regulatory T (Treg) cells on osteoclastogenesis and bone resorption. Treg cells that were isolated and purified from peripheral blood mononuclear cells (PBMCs) of healthy adults inhibited both the differentiation of osteoclasts (OCs) from human embryo bone marrow cells (BMCs) and the pit formation in a dose-dependent manner. In cell cocultures, the production levels of both interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-b1) were proportionally upregulated as the ratio of Treg cells to BMCs was increased, and the inhibition of OC differentiation and bone resorption by Treg cells was completely reversed by anti-IL-10 and anti-TGF-b1 antibodies. Treatment of BMC and Treg cell cocultures with 17b-estradiol (E2) at concentrations between 10 27 and 10 29 mol/l suppressed OC differentiation and bone resorption more efficiently than it did in cultures of BMCs alone; this enhanced suppression occurred via the stimulation of Treg cell IL-10 and TGF-b1 expression. These data suggest that Treg cells suppress OC differentiation and bone resorption by secreting IL-10 and TGF-b1. E2 enhances the suppressive effects of Treg cells on OC differentiation and bone resorption by stimulating IL-10 and TGF-b1 secretion from these cells. Therefore, Treg cell-derived IL-10 and TGF-b1 are likely involved in the regulation of E2 on bone metabolism and represent potential therapeutic targets for the treatment of postmenopausal osteoporosis (PMO).

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Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells

Cited by 147 publications

References 26 publications

Regulatory T Cells Protect from Local and Systemic Bone Destruction in Arthritis

Regulatory T Cells Protect from Local and Systemic Bone Destruction in Arthritis

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

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