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Antigen-non-specific regulation centered on CD25^(+)Foxp3^(+) Treg cells

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Cellular & Molecular Immunology 2010年第6期7卷 414-418页

作者： Gangzheng Hu Zhongmin Liu Changqing zheng song guo zheng Key Laboratory of Stem Cell Biology Institute of Health SciencesShanghai Institutes for Biological SciencesChinese Academy of Sciences/Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Gastroenterology Shengjing HospitalChina Medical UniversityShenyangChina Immune Tolerance and Regulation Center Shanghai East Hospital at Tongji UniveristyShanghaiChina Division of Rheumatology/Immunology Department of MedicineKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA

CD25^(+)Foxp3^(+) regulatory T cells(Tregs)are of special interest in immunology because of their potent inhibitory *** fundamental aspects of Tregs,including their antigenic profile,development and peripheral homeostasis,remain highly ***,we propose a Treg-centered antigen-non-specific immunoregulation model focused on the T-cell system,particularly on CD41 T *** T-cell pool consists of naive T cells(Tnais),Tregs and effector T cells(Teffs).Regardless of antigen specificity,the ratio of the activated T-cell subsets(Treg/Teff/Tnai)and their temporal and spatial uniformity dictate the differentiation of *** Tregs inhibit the activation,proliferation,induction and activity of Teffs;in contrast,activated Teffs inhibit the induction of Tregs from Tnais but cooperate with Treg-specific antigens to promote the proliferation and activity of *** many cases,these interactions are antigen-non-specific,whereas the activation of both Tregs and Teffs is *** T-cell subsets are essential for the maintenance of adaptive immune responses,but the antigen-non-specific interactions among T-cell subsets may be more important during the establishment of the adaptive immune system to a newly encountered *** is especially important when new and memory antigens are presented closely—both temporally and spatially—to T cells,because there are always baseline levels of activated Tregs,which are usually higher than levels of memory T cells for new *** on this hypothesis,we further infer that,under physiological conditions,Tregs in lymph nodes mainly recognize antigens frequently released from draining tissues,and that these self-reactive Tregs are commonly involved in the establishment of adaptive immunity to new antigens and in the feedback control of excessive responses to pathogens.

关键词： antigen immune regulation tolerance Treg

Induced Foxp3^(+)regulatory T cells:a potential new weapon to treat autoimmune and inflammatory diseases?

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Journal of Molecular Cell Biology 2012年第1期4卷 22-28页

作者： Qin Lan Huimin Fan Valerie Quesniaux Bernhard Ryffel Zhongmin Liu song guo zheng Medicine Translation Center Shanghai East HospitalTongji UniversityShanghai 200120China Division of Rheumatology and Immunology Department of MedicineUniversity of Southern CaliforniaKeck School of MedicineLos AngelesCA 90033USA UMR6218 Molecular ImmunologyUniversity and CNRS3b rue de la FerollerieOrleans F-45071France

Foxp3^(+)T regulatory cells(Tregs)consisting of natural and induced Treg subsets play a crucial role in the maintenance of immune homeostasis against *** actions designed to correct defects in numbers or functions of Tregs may be therapeutic in the treatment of autoimmune *** recent studies demonstrated that natural Tregs are instable and dysfunctional in the in-flammatory condition,induced Tregs(iTregs)may have a different *** we review the progress of iTregs,particularly focus on their stability and function in the established autoimmune *** advantage of iTregs as therapeutics used under inflammatory conditions is *** generation and manipulation of iTregs used for cellular therapy may provide a promise for the treatment of many autoimmune and inflammatory diseases.

关键词： autoimmune and inflammatory diseases immunoregulation regulatory T cells TGF-b Foxp3 Th17 cells atRA

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

Advances in the role of follicular T helper cells in graft versus host diseases

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Liver Research 2017年第2期1卷 131-134页

作者： Maogen Chen Xiaohong Lin Julie Wang Nancy Olsen song guo zheng Division of Immunology and Rheumatology Keck School of Medicine at University of Southern CaliforniaCAUSA Organ Transplant Center First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology GuangzhouChina Guangdong Provincial International Cooperation Base of Science and Technology(Organ Transplantation) GuangzhouChina Center for Clinical Immunology at Sun Yat-sen University GuangzhouChina Division of General Surgery The Eastern Hospital of the First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Division of Rheumatology Penn State Milton S.Hershey Medical CenterHersheyPAUSA

Graft versus host disease(GVHD)is a refractory complication of allogeneic hematopoietic stem cell transplantation for the treatment of malignant and non-malignant hematopoietic *** cascade responses and cellular immune reactions are the major factors underlying GVHD *** producing the cytokine,interleukin(IL)-21 are crucial players involved in injured tissues in GVHD *** T helper 17 cells,follicular T helper(Tfh)cells are a new source of IL-21 and play a vital role in GVHD *** cell function is mostly regulated by T-follicular regulatory(Tfr)cells that are also located in the germinal *** review highlights recent advances in the role of Tfh and Tfr cell function in GVHD *** insights are provided into the potential for clinical application in GVHD prevention and treatment.

关键词： Graft versus host disease(GVHD) Allogeneic hematopoietic stem cell transplantation Interleukin-21 Follicular T helper(Tfh)cell

microRNA-21a-5p/PDCD4 axis regulates mesenchymal stem cell-induced neuroprotection in acute glaucoma

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Journal of Molecular Cell Biology 2017年第4期9卷 289-301页

作者： Wenru Su Zuohong Li Yu Jia Yingting Zhu Wenjia Cai Peixing Wan Yingying Zhang song guo zheng Yehong Zhuo State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangzhou 510060 China Department of Clinic Immunology The Third Affiliated Hospital at Sun Yat-sen University Guangzhou 510630 China Division of Rheumatology Department of Medicine Penn State Milton S. Hershey Medical Center Hershey PA 17033 USA

Mesenchymal stem ceils （MSCs） have been demonstrated to have promising therapeutic benefits for a variety of neurological dis- eases; however, the underlying mechanisms are poorly understood. Here, we showed that intravitreal infusion of MSCs promoted retinal ganglion cell （RGC） survival in a mouse model of acute glaucoma, with significant inhibition of microglial activation, production of TNF-α, IL-1β, and reactive oxygen species, as well as caspase-8 and caspase-3 activation. In vitro, MSCs inhibited both caspase-8-mediated RGC apoptosis and microgUal activation, partly via the action of stanniocalcin 1 （STCl）. Furthermore, we found that microRNA-21a-Sp （miR-21） and its target, PDCD4, were essential for STC1 production and the neuroprotective property of MSCs in vitro and in vivo. Importantly, miR-21 overexpression or PDCD4 knockdown augmented MSC-mediated neuroprotective effects on acute glaucoma. These data highlight a previously unrecognized neuroprotective mechanism by which the miR-21/ PDCD4 axis induces MSCs to secrete STC1 and other factors that exert neuroprotective effects. Therefore, modulating the miR- 21/PDCD4 axis might be a promising strategy for clinical treatment of acute glaucoma and other neurological diseases.

关键词： mesenchymal stem ceils microRNA neuroprotection glaucoma neurological diseases

How regulatory T cells sense and adapt to inflammation

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Cellular & Molecular Immunology 2015年第5期12卷 519-520页

作者： Bin Li song guo zheng Key Laboratory of Molecular Virology andImmunology Unit of Molecular ImmunologyInstitut Pasteur of Shanghai Shanghai Institutesfor Biological Sciences Chinese Academy ofSciences Shanghai 200025 China Division of Rheumatelogy Penn State Milton S.Hershey Medical Center Hershey PA 17033USA

The immune system exists in harmony and also with the potential for dynamic control in healthy individuals. Our healthy body needs to sense the presence of microbes and react through both innate and adaptive immunity to elim- inate infection. How our immune system senses the initiation, progression, and ter- mination of the inflammatory process is critical for maintaining immune home- ostasis. Thanks to the elegant experi- mental progress in using conditional knockout animal models, we have,

关键词：感染免疫系统模型动物卫生服务需求炎症胰岛素

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

Inflammasome-IL-1-Th17 response in allergic lung inflammation

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Journal of Molecular Cell Biology 2012年第1期4卷 3-10页

作者： Anne-Gaelle Besnard Dieudonnee Togbe Isabelle Couillin Zoming Tan song guo zheng Francois Erard Marc Le Bert Valerie Quesniaux Bernhard Ryffel University of Orleans and Molecular Immunology and Embryology CNRS UMR6218OrleansFrance Artimmune SAS Centre d’InnovationOrleansFrance Division of Rheumatology and Immunology Department of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA University of Cape Town IIDMMCape TownSouth Africa

Allergic asthma has increased dramatically in prevalence and severity over the last three *** clinical and experimental data support an important role of Th2 cell response in the allergic *** investigations revealed that airway exposure to allergen in sensitized individuals causes the release of ATP and uric acid,activating the NLRP3 inflammasome complex and cleaving pro-IL-1b to mature IL-1b through *** production of pro-IL-1b requires a toll-like receptor(TLR)4 signal which is provided by the ***-1b creates a pro-inflammatory milieu with the production of IL-6 and chemokines which mobilize neutrophils and enhance Th17 cell differentiation in the ***,we review our results showing that NLRP3 inflammasome activation is required to develop allergic airway inflammation in mice and that IL-17 and IL-22 production by Th17 cells plays a critical role in established ***,inflammasome activation leading to IL-1b production contributes to the control of allergic asthma by enhancing Th17 cell differentiation.

关键词： asthma NLRP3 inflammasome IL-1 Th17 cells IL-17 IL-22

Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions

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Cellular & Molecular Immunology 2017年第6期14卷 521-528页

作者： Jian Gu Xuhao Ni Xiongxiong Pan Hao Lu Yunjie Lu Jie Zhao song guo zheng Keli L Hippen Xuehao Wang Ling Lu Translational Medicine Research Center Affiliated Jiangning Hospital and Liver Transplantation Center First Affiliated Hospital Nanjing Medical University Nanjing 210029 China University of Minnesota Cancer Center and Division of Bone Marrow Transplantation Department of Pediatrics University of Minnesota Minneapolis MN 55455 USA Division of Rheumatology Penn State Milton S. Hershey Medical Center Hershey PA 17033 USA

Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Thl and Th17 cells. Studies have confirmed that natural CD4＋Foxp3＋ Tregs were unstable and dysfunctional in the presence of pro-inflammatory cytokines. In the current study, human CD39hi Tregs and CD39low Tregs were sorted from Tregs in vitro after 7 days of expansion. The functions of both Treg subsets were investigated under inflammatory conditions in vitro and in vivo. In the presence of IL-1β and IL-6, cultured CD4＋CD39hi Tregs maintained stable forkhead box protein 3 expression, whereas CD4＋CD39low Tregs lost Foxp3 expression and trans-differentiated into Thl or Th17 cells. Decreased IL-1βR and IL-6R expression on the CD39hi Tregs was the primary mechanism responsible for Treg stability. In addition, reduced activation of downstream molecules, such as STAT1 and STAT3, through the modulation of CpG demethylation played an important role. Finally, human CD4＋CD39hi Tregs but not CD4＋CD39low Tregs protected against xenograft versus host disease in model mice. These results strongly implied the physiological importance of CD39 expression and suggested that manipulation of CD39hi Tregs might represent a novel strategy for the treatment of autoimmune diseases.

关键词： CD39 stability Tregs xeno-GVHD