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ABSTRACT: Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a major role in tumor-induced immunosuppression, which hampers effective immunotherapeutic approaches. β-Glucans have been reported to function as potent immunomodulators to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. Here we investigated the effect of particulate β-glucans on MDSCs and found that β-glucan treatment could promote the differentiation of M-MDSCs (monocytic MDSCs) into a more mature CD11c(+) F4/80(+) Ly6C(low) population via dectin-1 pathway in vitro, which is NF-κB dependent, and the suppressive function of M-MDSCs was significantly decreased. Treatment of orally administered yeast-derived particulate β-glucan drastically down-regulated MDSCs but increased the infiltrated DCs and macrophages in tumor-bearing mice, thus eliciting CTL and Th1 responses, inhibiting the suppressive activity of regulatory T cells, thereby leading to the delayed tumor progression. We show here for the first time that β-glucans induce the differentiation of MDSCs and inhibit the regulatory function of MDSCs, therefore revealing a novel mechanism for β-glucans in immunotherapy and suggesting their potential clinical benefit.
European Journal of Immunology 02/2013; · 5.10 Impact Factor
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Jie Tian,
Jie Ma,
Ke Ma,
Bin Ma,
Xinyi Tang,
Samuel Essien Baidoo,
Jia Tong,
Jun Yan,
Liwei Lu,
Huaxi Xu,
Shengjun Wang
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ABSTRACT: β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL), a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses.
In this study, we found that whole β-glucan particles (WGPs) could activate dendritic cells (DCs) via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg)-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL) responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression.
These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development.
PLoS ONE 01/2012; 7(10):e46936. · 4.09 Impact Factor
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Jie Ma,
Chenlu Zhu,
Bin Ma, Jie Tian,
Samuel Essien Baidoo,
Chaoming Mao,
Wei Wu,
Jianguo Chen,
Jia Tong,
Min Yang,
Zhijun Jiao,
Huaxi Xu,
Liwei Lu,
Shengjun Wang
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ABSTRACT: Follicular helper T (Tfh) cells are recognized as a distinct CD4(+) helper T-cell subset, which provides for B-cell activation and production of specific antibody responses, and play a critical role in the development of autoimmune disease. So far, only one study investigated the circulating Tfh cells increased in a subset of SLE patients. Since relatively little is known about the Tfh cells in rheumatoid arthritis (RA) patients, in this study, Tfh-cell frequency, related cytokine IL-21, and transcription factor Bcl-6 were investigated in 53 patients with RA and 31 health controls. Firstly, we found that the frequency of CD4(+)CXCR5(+)ICOS(high) Tfh cells was increased significantly in the peripheral blood of RA patients, compared with that in healthy controls. It is known that Tfh cells are critical for directing the development of an antibody response by germinal centers B cells; secondly, we observed that the Tfh-cell frequency is accompanied by the level of anti-CCP antibody in RA patients. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in RA patients was increased. Taken together, these findings have shown that the increased frequency of circulating Tfh cells is correlated with elevated levels of anti-CCP antibody, indicating the possible involvement of Tfh cells in the disease progression of RA.
Clinical and Developmental Immunology 01/2012; 2012:827480. · 1.84 Impact Factor
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Shengjun Wang,
Ye Shi,
Min Yang,
Jie Ma, Jie Tian,
Jianguo Chen,
Chaoming Mao,
Zhijun Jiao,
King-Hung Ko,
Samuel Essien Baidoo,
Huaxi Xu,
Zichun Hua,
Liwei Lu
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ABSTRACT: Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively affects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune reactions, but the underlying mechanisms by which GITR activation promotes arthritic progression remain largely unclear. In this study, we found that collagen-induced arthritis mice treated with the ligand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of arthritic symptoms and joint damage, in which significantly increased Th17 cells in both spleen and draining lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased RORγt mRNA expression was induced from naïve CD4(+) T cells when cultured with GITRL. Consistently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleukin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhancement of the expansion of Th17 cells.
American Journal Of Pathology 12/2011; 180(3):1059-67. · 4.89 Impact Factor
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ABSTRACT: Follicular helper T (Tfh) cells exert an important role in the autoimmune diseases.
Our study aimed to explore the role of Tfh cells in patients with autoimmune thyroid disease (AITD).
Tfh cell is a new subset regulating the antibody production of B cell. Previous studies implicated CD4+CXCR5+ICOShigh or CD4+CXCR5+PD-1high as the markers of circulating Tfh cells. Sixty-five patients with AITD and 30 healthy controls were enrolled in the current study. The percentages of circulating Tfh cells were assessed by flow cytometry. The correlation between the percentages of CD4+CXCR5+ICOShigh T cells and the levels of autoantibodies or hormones was also analyzed. Additionally, polyphasic methods were applied to investigate the status of Tfh cells in thyroid glands of Hashimoto's thyroiditis patients.
Increased percentages of circulating Tfh cells in AITD patients were detected, and a positive correlation between the percentages of circulating Tfh cells and the serum concentrations of anti-TSH receptor-Ab/thyroperoxidase-Ab/thyroglobulin-Ab was confirmed. A positive or modest relationship between the percentages of circulating Tfh cells and serum free T3 or free T4 was revealed in Graves' disease patients. Additionally, follow-up analysis indicated that in some Graves' disease patients the percentage of circulating Tfh cells decreased after treatment. Furthermore, a certain number of CD4+CXCR5+ICOShigh T cells together with enhanced expression of IL-21 and Bcl-6 mRNA were detected in thyroid tissues from Hashimoto's thyroiditis patients.
The current study discovered an increased frequency of Tfh cells in AITD patients, which implies that this cell subset might play an important role in the pathogenesis of AITD.
The Journal of clinical endocrinology and metabolism 12/2011; 97(3):943-50. · 6.50 Impact Factor
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Jie Tian,
Jie Ma,
Shengjun Wang,
Jun Yan,
Jianguo Chen,
Jia Tong,
Chaoyang Wu,
Yingzhao Liu,
Bin Ma,
Chaoming Mao,
Zhijun Jiao,
Qixiang Shao,
Liwei Lu,
Huaxi Xu
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ABSTRACT: β-Glucans have been shown to enhance immune responses for centuries, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Dectin-1, the C-type lectin receptor for β-glucan, is expressed abundantly on dendritic cells (DCs). Activation of DCs via Dectin-1 can lead to the maturation of DC, inducing both innate and adaptive immune responses against tumor development and microbial infection. In this study, we found that particulate yeast-derived β-glucans could induce the maturation of murine dendritic cell line D2SC/1 cells and increase the expression of mGITRL on D2SC/1 cells via Dectin-1/Syk pathway in a dose dependent manner. Furthermore, we demonstrated that the increased mGITRL on D2SC/1 cells could impair the suppressive activity of CD4(+)CD25(+) regulatory T cells (Tregs) and enhance the proliferation of CD4(+)CD25(-) effector T cells (Teffs). These findings suggest that particulate β-glucan can be used as immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate immune suppressive activity, leading to a more efficient defense mechanism against tumor development or infectious diseases.
Cellular Immunology 05/2011; 270(2):183-7. · 1.97 Impact Factor
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ABSTRACT: To express the mouse glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) protein with Bac-to-Bac baculovirus expression system.
GITRL gene was obtained by double digestion using EcoR I and Sal I and cloned into the baculovirus transfer vector pFastBacHTA. Then the pFastBacHTA was transformed into competent 10BacTM E.coli cells. The transposition occurred between pFastBacHTA and bacmid and a recombinant bacmid was obtained. The positive clones were picked out and the recombinant bacmid was isolated, and then complete transfected into Tn cells for producing complete recombinant baculovirus. The baculoviral stock was amplified and the GITRL protein was expressed.
The presence of GITRL gene containing the recombinant bacmid was verified by PCR and gene sequencing. The cytopathic effect (CPE) displayed in the transfected Tn cells assumed that the transfection was successful. Western blot analysis showed that the molecular weight of mGITRL protein was about 20 KD.
The GITRL protein is expressed successfully with Bac-to-Bac baculovirus expression system, which may lay the foundation for further study on biological activity and function of GITRL protein.
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 04/2011; 27(4):405-7.
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ABSTRACT: To construct recombinant adenovirus vector pAdEasy-GFP-GITRL and detect the viral titer.
GITRL gene was obtained by double digestion using Bgl II and Sal I, and cloned into the baculovirus transfer vector(pAdtrack-CMV), then the recombinant adenovirus vector (pAdtrack-CMV-GITRL) was digested by restrictive endoenzyme Pme I. The linear recombinant adenorirus vector and pAdEasy-1 were cotransfected into HEK293 cells by co-precipitate of calcium phosphate. Recombinant adenovirus was packaged and purified in HEK293A cells.
Recombinant adenovirus vector pAdEasy-GFP-GITRL was constructed successfully and high titer of recombinant adenovirus was obtained (2.0 x 10⁹ pfu/mL). Western blotting analysis also revealed the expression of GITRL by recombinant adenovirus vector.
The construction of recombinant adenovirus vector pAdEasy-GFP-GITRL and recombinant adenovirus will facilitate the potential GITRL gene therapy.
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 11/2010; 26(11):1075-7.
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Dawei Cui,
Shengjun Wang,
Yu Chen,
Jia Tong,
Jie Ma,
Li Tang,
Xianzhi Yang,
Ye Shi, Jie Tian,
Liwei Lu,
Huaxi Xu
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ABSTRACT: Glucocorticoid-induced tumor-necrosis factor receptor (GITR) and its ligand, GITRL, play significant roles in regulating immune responses. It is clear that human soluble GITRL (hsGITRL) transduces signal activity through multiple oligomerization states. To develop human soluble trimeric GITRL protein as a potential therapeutic target, we explored the link of the isoleucine-zipper (ILZ) motif to the N-terminus of the human soluble GITRL with two leucine sequences. hsGITRL, with the ILZ motif (ILZ-hsGITRL), was firstly expressed in Escherichia coli, which exhibited a predominant trimer when identified by Sephadex G-100 filtration and non-reducing SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The significantly higher biological activity of the ILZ-hsGITRL compared with hsGITRL was confirmed by CD4(+) T proliferation, interferon-gamma (IFN-gamma) secretion and binding activity assay. To reveal and compare the underlying mechanisms, the level of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation was examined, indicating that ILZ-hsGITRL induced more persistent and stronger ERK1/2 activation than hsGITRL. In conclusion, the incorporation of an ILZ motif could markedly improve the costimulation of hsGITRL.
Cellular & molecular immunology 03/2010; 7(4):316-22. · 2.99 Impact Factor
