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TGF-β-induced CD4+FoxP3+regulatory T cell-derived extracellular vesicles modulate Notch1 signaling through miR-449a and prevent collagen-induced arthritis in a murine model

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Cellular & Molecular Immunology 2021年第11期18卷 2516-2529页

作者： Jingrong Chen Feng Huang Yuluan Hou Xiaorong Lin Rongzhen Liang Xiaojiang Hu Jun Zhao julie wang Nancy Olsen Song Guo Zheng Department of Clinical Immunology The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdongChina Department of Internal Medicine Division of RheumatologyThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdongChina Division of Rheumatology Department of MedicinePenn State University Hershey Medical CenterHersheyPAUSA

CD4^(+)FOXP3^(+)Treg cells are central to the maintenance of self-tolerance and can be defective in *** autoimmune rheumatic diseases,dysfunctional self-tolerance,is to a large extent,caused by insufficient Treg-cell *** nTregs have therapeutic effects in vivo,their relative scarcity and slow rate of in vitro expansion hinder the application of nTreg *** was previously reported that EVs contribute significantly to the suppressive function of FOXP3^(+)Treg *** that the stability and plasticity of nTregs remain major challenges in vivo,we established EVs derived from in vitro TGF-β-induced Treg cells(iTreg-EVs)and assessed their functions in a murine model of autoimmune *** results demonstrated that iTreg-EVs preferentially homed to the pathological joint and efficiently prevented the imbalance in Th17/Treg cells in arthritic ***,we found that miR-449a-5p mediated Notch1 expression modulation and that miR-449a-5p knockdown abolished the effects of iTreg-EVs on effector T cells and regulatory T cells in vitro and in *** together,our results show that iTreg-EVs control the inflammatory responses of recipient T cells through miR-449a-5p-dependent modulation of Notch1 and ameliorate the development and severity of arthritis,which may provide a potential cell-free strategy based on manipulating iTreg-EVs to prevent autoimmune arthritis.

关键词： EVs iTreg Arthritis Th17 MicroRNA Notch1

A protocol to develop T helper and Treg cells in vivo

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Cellular & Molecular Immunology 2017年第12期14卷 1013-1016页

作者： Weiqian Chen Zhenjian Xu Yongjiang Zheng julie wang Wenbin Qian Nancy Olsen David Brand Jin Lin Song Guo Zheng Division of Rheumatology First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang Province 310003China Division of Rheumatology Department of MedicinePenn State University Hershey College of Medicine HersheyHersheyPA 17033USA Department of Clinical Immunology Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510120China Division of Hematology First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang Province 310003China Research Service Memphis VA Medical CenterMemphisTNUSA

An understanding of the development and function of T helper(Th)1,Th17 and regulatory T(Treg)cells is critical toward revealing pro-inflammatory immune responses,especially in autoimmune ***,there is no standard protocol to monitor the development of these cells over time in *** protocol details a method to generate Th1,Th17,and Treg cells in a T cell-induced colitis model in vivo and monitor their dynamic changes,which can be used for further investigations in their development from naive CD4+T cells in specific gene knockouts and background strains.

关键词： Th17 vivo Treg

High salt diet accelerates the progression of murine lupus through dendritic cells via the p38 MAPK and STAT1 signaling pathways

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2082-2094页

作者： Ze Xiu Xiao Xiaojiang Hu Ximei Zhang Zhigang Chen julie wang Ke Jin Feng Lin Cao Baoqing Sun Joseph A.Bellanti Nancy Olsen Song Guo Zheng Department of Clinical Immunology The Third Affiliated Hospital at Sun Yat-sen University510630 GuangzhouChina Department of Internal Medicine Ohio State University College of Medicine and Wexner Medical CenterColumbusOH 43210USA Department of Medicine Penn State College of MedicineHersheyPA 17033USA Laboratory of Human Diseases and Immunotherapy West China HospitalSichuan UniversityChengduChina Department of Internal Medicine The First Hospital of Harbin Medical UniversityHarbinChina Department of Allergy and Clinical Immunology The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of Pediatrics and Microbiology-Immunology Georgetown University Medical CenterWashingtonDCUSA

The increased incidence of systemic lupus erythematosus(SLE)in recent decades might be related to changes in modern dietary *** sodium chloride(NaCl)promotes pathogenic T cell responses,we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases,including *** the importance of dendritic cells(DCs)in the pathogenesis of SLE,we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE *** used an induced lupus model in which bone marrow-derived dendritic cells(BMDCs)were incubated with activated lymphocyte-derived DNA(ALD-DNA)and transferred into C57BL/6 recipient *** observed that a high-salt diet(HSD)markedly exacerbated lupus progression,which was accompanied by increased DC *** treatment also stimulated the maturation,activation and antigenpresenting ability of DCs in *** of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced *** mice had increased production of autoantibodies and proinflammatory cytokines,more pronounced splenomegaly and lymphadenopathy,and enhanced pathological renal *** p38 MAPK–STAT1 pathway played an important role in NaClinduced DC immune *** together,our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK–STAT1 signaling pathway and exacerbates the features of ***,changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.

关键词： STAT1 lupus prevention

Human Gingiva-Derived Mesenchymal Stem Cells regulated the balance of osteoclasts and osteoblasts by CD39 in treatment of osteoporosis

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Human Gingiva-Derived Mesenchymal Stem Cells regulated the b...

第十三届全国免疫学学术大会

作者： Wenbin Wu julie wang Bernhard Ryffel Song Guo Zheng Sun Yat-sen University Penn State University France CNRS

The cytokines such as RANKL, TNF-α and the immune cells such as Treg and Th17 play an important role in the incidence of *** existing treatment failed to reduce the risk of fractures in ***, we need to find more effective *** evaluated the therapeutic potential of GMSC inhibition in osteoporosis induced by estrogen deficiency, the most prevalent cause of osteoporosis worldwide, using the ovariectomy(OVX)-induced osteopenia *** explore therapeutic potential, OVX was performed in adult C57 BL/6 J mice after complete skeletal remodeling, and GMSC therapy initiated 2 weeks after *** 8 weeks of treatment, the distal femoral trabecular bone was sparse and discontinuous in OVX group, and GMSC showed a clear therapeutic effect in bone density, trabecular BV/TV, trabecular *** identify the mechanism of GMSC function in osteoporosis in vivo, we analyzed the role of CD39 signals, since we found that GMSCs inhibited osteoclast differentiation through CD39 signals and CD39 inhibitors(POM-1) inhibited the osteogenic potential of GMSCs in ***, POM-1 almost completely abolished the therapeutic effect of GMSCs on *** results highlight the key role of CD39 in the GMSCs function.

关键词： GMSC osteoclast osteoporosis CD39

Essential kinases and Transcriptional Regulators and their Roles in Autoimmunity

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Essential kinases and Transcriptional Regulators and their R...

第十三届全国免疫学学术大会

作者： Yanan Deng julie wang Joseph A Bellanti Bernhard Ryffel Song Guo Zheng Sun Yat-sen University Penn State Univ Georgetown Univ France CNRS

Kinases and transcriptional regulators which are fundamental components of cell signaling, they have expressed on many kinds of immune cells, and are involved in the secretion of cytokines, cell proliferation, differentiation and apoptosis, both have important roles in the biological response, Autoimmune diseases include at least 80 diseases, and often controlled by complex genetic and environmental factors. Its pathogenesis is generally due to the breaking of autoimmune tolerance so as to generate an abnormal response to autoantigen. It is a major cause of autoimmune diseases that the balance between self-reactive cells and regulatory cells been broken. Abnormal expression of kinases or transcriptional regulators are often found in aberrant autoimmune cells. These abnormal expressions of kinases or transcriptional regulators can over-activate the function of the self-reactive cells to produce inflammatory factors or down-regulate the activity of regulatory cells, thus producing autoimmune diseases. In this review mainly introduce five kinds of kinase and transcriptional regulator related to autoimmune diseases;namely Janus kinases family(JAK2,TYK2), Fork head box protein 3(FOXP3), the Retinoid-related orphan receptor γ(ROR γ) and T-box expressed in T cells(T-bet). We provide a mechanistic insight into how these kinases and transcriptional regulators affect the immune cells related to autoimmune diseases, as well as the current drug design targeting these kinases and transcriptional regulators to improve the autoimmune disease and inflammatory response, and also discussed the deficiencies in the current research.

关键词： autoimmunity kinases transcriptional factors

Crucial role of metabolism enzymes Acsl6 and Acsbg1 in the development of TGF-β-induced Treg cells

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Crucial role of metabolism enzymes Acsl6 and Acsbg1 in the d...

第十三届全国免疫学学术大会

作者： Jun Zhao julie wang Bernhrad Ryffel Joseph A Bellanti Song Guo Zheng Sun Yat-sen University Penn State Univ France CNRS Georgetown Univ

Regulatory T cells(Tregs), a distinct T-cell lineage characterized by their expression of Foxp3, play important roles in immunological regulation including preventing autoimmune diseases and alleviating allergic diseases. It has been shown that Foxp3 can be induced in T cell receptor(TCR)-stimulated CD25-non-regulatory T cells by TGF-β, but its underling molecular mechanism remains unclear. Recently, many studies have proved that differentiated mouse Tregs display low glycolytic flux and high oxidation rate of lipid when compared with other T-cell subsets, suggesting the possibility that TGF-β might induce Treg difference through affecting the metabolism pathway in T cells. Therefore, we screened T cells which had been treated or non-treated with TGF-β for different expression of metabolic genes by RNA sequence and real time PCR, and found that the expression of Acsl6 and Acsbg1, the two critical activators mediating long-chain fatty acid transfer to acyl-coenzyme A, significantly increased in TGF-β-treated group. Consistently, HPLC-MS data verified that Nervonic acid(24:1), one of the long-chain fatty acids, downregulated in TGF-β-treated group. Furthermore, knockdown of Acsl6 and Acsbg1 by specific siRNA suppressed the differentiation of Tregs induced by TGF-β, implying that TGF-β could upregulate the expression of Acsl6 and Acsbg1, and then activate fatty acid oxidization and finally result in Tregs differentiation. In conclusion, this study demonstrates the molecular mechanism by which TGF-β induces Tregs differentiation, thus paves a solid road for Tregs-based therapy in patients with autoimmune and inflammatory diseases in the future.

关键词： Treg cells TGF-β metabolism fatty acid

ITK inhibitor BMS509744 ameliorates Collagen-Induced Arthritis via shifting the balance between Th17 and regulatory Th17 cells

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ITK inhibitor BMS509744 ameliorates Collagen-Induced Arthrit...

第十三届全国免疫学学术大会

作者： Ye Chen julie wang Weishan Huang David Brand Avery August Song Guo Zheng Sun Yat-sen University Penn State Univ Cornell Univ Univ of Tennessee

Rheumatoid arthritis(RA) is a chronic inflammation disease that cannot be cured and current approaches have the severe side effects. Although the pathogenesis is not completely understood, many studies have suggested that the imbalance between Th17 cells/inflammatory cytokines and suppressive Foxp3 T regulatory cells(Tregs) is associated with the pathogenesis and development in RA progression. ITK is involved in signaling cascades mediating T-lymphocyte proliferation, differentiation, and migration and pro-inflammatory cytokine production. The small molecule BMS509744 covalently binds ITK and inhibits the kinase activity of ITK. Here we report that BMS509744 effectively Skewed Th cells to Treg under Th17 differentiation conditions and promote Treg induction under Treg differentiation condition, and give rise to increased Foxp3 expression across TCR doses under Th17 and Treg condition, these effects can be reversed by SGK1 inhibitor. Moreover, we found that Itk inhibitor decreased mTor activity and altered metabolic marker HIF1 a and SLC3 a which regulate the balance between Th17 and Treg cells. Additionally, BMS509744 effectively ameliorate collagen-induced arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominance. Our result indicates that BMS509744 is an effective RA therapeutic.

关键词： Itk Th17 Treg SGK1 CIA

The co-stimulatory molecule B7-H1 ameliorated the function of Human Gingiva-Derived Mesenchymal Stem Cells through IL-10 on CIA mice model

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The co-stimulatory molecule B7-H1 ameliorated the function o...

第十三届全国免疫学学术大会

作者： Zexiu Xiao julie wang Bernhard Ryffel Joseph Bellanti Oliva Lawless Song Guo Zheng Sun Yat-sen University Penn State University France CNRS Georgetown University

Human Gingiva-derive mesenchymal Stem Cells(GMSCs) have shown anti-inflammatory and immunomodulatory effects on autoimmune and other inflammatory diseases. We have recently reported that GMSCs have strong capacity to suppress human PBMC-initiated xenogenic GVHD mice model, collagen-induced arthritis, Streptozoticin-induced T1 DM mice model, and GMSCs also ameliorated atherosclerosis in *** mechanism of suppression effect of Gingiva-derive mesenchymal Stem Cells(GMSCs) remains less clear. We herein demonstrate that co-stimulatory molecule B7-H1(PD-L1) on GMSCs exert the immune-suppressive function and results in significantly improved therapeutic effects of GMSCs on autoimmune diseases. CIA was induced with type II bovine collagen(CII) and CFA in DBA/1 J mice. GMSCs were injected I.V. into mice on day 14 after immunization. GMSCs pretreated with B1-H1 blocking antibody for 24 hours. B7-H1 high or low expression subsets were sorted by *** We showed that B7-H1+ GMSC subset had stronger suppression effects on T cells proliferation compared with B7-H1 GMSC. Additionally, the anti-inflammatory capacity of GMSCs abolished when B7-H1 was blocked in collagen induced arthritis DBA1 mice model. B7-H1 promoted migration of GMSCs, and B7-H1 ameliorated immunomodulatory function of GMSCs through upregulated STAT-3 level induced IL-10 *** findings suggest the vital effect of B7-H1 on the Gingiva-derive mesenchymal stem cells and provide a promising approach for the treatment of autoimmune diseases.

关键词： GMSC B1-H1 lupus

DBC1影响Treg/Th17细胞平衡参与胶原诱导关节炎小鼠的发病

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DBC1影响Treg/Th17细胞平衡参与胶原诱导关节炎小鼠的发病

第十二届全国免疫学学术大会

作者：雒扬 julie wang 郑颂国中山大学附属第三医院宾夕法尼亚州立大学风湿免疫性疾病研究中心

目的:Th17细胞介导炎症反应,调节性T细胞(Treg)抑制炎症反应,介导免疫耐受。Treg和Th17细胞比例失衡参与多种自身免疫性疾病的发病。我们曾首次报道乳腺癌缺失因子1(DBC1)可与Treg特异性转录因子Foxp3结合,下调Treg中Foxp3的表达,使nTre... 详细信息

目的:Th17细胞介导炎症反应,调节性T细胞(Treg)抑制炎症反应,介导免疫耐受。Treg和Th17细胞比例失衡参与多种自身免疫性疾病的发病。我们曾首次报道乳腺癌缺失因子1(DBC1)可与Treg特异性转录因子Foxp3结合,下调Treg中Foxp3的表达,使nTreg向Th17细胞转化,从而影响自身免疫性脑脊髓膜炎的发病。因此,DBC1是否也可同样促进TGF-β诱导的调节性T细胞(iTreg)转化为Th17细胞;其自身是否可直接调控Th17细胞的分化和增殖;是否也通过影响Treg/Th17细胞的平衡参与胶原诱导小鼠关节炎(CIA)的发生发展等,均未有报道。方法:首先,我们过继转输来自DBC1和DBC1小鼠的并带有Foxp3-GFP和IL-17-RFP荧光的幼稚性T细胞(naive T cells)到Rag1小鼠,动态跟踪这群细胞在体内的分化,同时与体外诱导(in vitro)na(i|¨)ve T转变为Th7,Th1,iTreg细胞的结果对比,观察DBC1对T细胞亚群分化和增殖的作用。其次,利用骨髓嵌合体模型进一步证实上述结果。最后,我们杂交B6和DBA1小鼠得到DBA1 DBC1以及DBA1 DBCFoxp3-GFP小鼠并诱导关节炎,观察DBC1是否影响关节炎的发病并探讨其分子机制。结果:我们利用Rag1小鼠和骨髓嵌合体两种模型,发现DBC1敲除的na(i|¨)ve T在体内更多的表达Foxp3-GFP,而IL-17-RFP以及IFN-γ(Th1细胞)明显减少,其与在体外诱导na(i|¨)ve T转变为Th17,Th1,iTreg细胞分化的结果一致。因此我们用牛胶原免疫DBA1 DBC1小鼠诱导关节炎,发现其疾病严重程度和关节破坏等明显轻于正常小鼠。同时,DBC1敲除CIA中Treg比例显著增加(以iTreg为主),Th17细胞明显减少;且DBC1CIA小鼠的Treg相比正常小鼠更稳定,具有更强的抑制能力。利用免疫共沉淀方法发现DBC1不仅降解Foxp3,同时可与RORγt(Th17特异性转录因子)结合,通过SIRT1-RORγt信号促进Th17细胞的分化与增殖。结论:DBC1负调控Treg细胞,促进Th17细胞的分化与增殖,改变Treg/Th17细胞动态平衡,影响关节炎的发生发展。因此DBC1可望成为治疗关节炎或其他自身免疫性疾病的新靶点。

关键词： DBC1 Treg Th17 CIA