title: TGF-β-Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism.
abstract: Foxp3(+) regulatory T cells (Treg) playing a crucial role in the maintenance of immune tolerance and prevention of autoimmune diseases consist of thymus-derived naturally occurring CD4(+)Foxp3(+) Treg cells (nTreg) and those that can be induced ex vivo with TGF-β (iTreg). Although both Treg subsets share similar phenotypes and functional characteristics, they also have potential biologic differences on their biology. The role of iTreg in regulating B cells remains unclear so far. The suppression assays of Treg subsets on activation, proliferation, and Abs production of B cells were measured using a Treg and B cell coculture system in vitro. Transwell and Ab blockade experiments were performed to assess the roles of cell contact and soluble cytokines. Treg were adoptively transferred to lupus mice to assess in vivo effects on B cells. Like nTreg, iTreg subset also directly suppressed activation and proliferation of B cells. nTreg subset suppressed B cell responses through cytotoxic manner related to expression of granzyme A, granzyme B, and perforin, whereas the role of iTreg subset on B cells did not involve in cytotoxic action but depending on TGF-β signaling. Furthermore, iTreg subset can significantly suppress Ab produced by lupus B cells in vitro. Comparison experiments using autoantibodies microarrays demonstrated that adoptive transfer of iTreg had a superior effect than nTreg subset on suppressing lupus B cell responses in vivo. Our data implicate a role and advantage of iTreg subset in treating B cell-mediated autoimmune diseases, boosting the translational potential of these findings.
authors.affiliation: Division of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Center for Clinic Immunology, Third Hospital, Sun Yat-sen University, Guangzhou 510630, China; szheng1@hmc.psu.edu anpxu@163.com.
authors.forename: Anping
authors.identifier: 0000-0003-3626-1619
authors.initials: A
authors.lastname: Xu
authors.affiliation: Division of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033;
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033; Division of Rheumatology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China;
authors.forename: Weiqian
authors.identifier: 0000-0003-3819-7841
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033;
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Clinic Immunology, Third Hospital, Sun Yat-sen University, Guangzhou 510630, China;
authors.forename: Youqiu
authors.identifier: 0000-0003-0505-8714
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Center for Clinic Immunology, Third Hospital, Sun Yat-sen University, Guangzhou 510630, China;
authors.forename: Feng
authors.identifier: 0000-0002-2255-3832
authors.initials: F
authors.lastname: Huang
authors.affiliation: Center for Clinic Immunology, Third Hospital, Sun Yat-sen University, Guangzhou 510630, China;
authors.forename: Liming
authors.initials: L
authors.lastname: Rong
authors.affiliation: Division of Rheumatology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China;
authors.forename: Jin
authors.identifier: 0000-0002-0978-0723
authors.initials: J
authors.lastname: Lin
authors.affiliation: Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, China;
authors.forename: Dahai
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Mei
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Quan-Zhen
authors.identifier: 0000-0002-7257-0489
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Unit of Molecular Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; and.
authors.forename: Bin
authors.identifier: 0000-0002-7640-8884
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033.
authors.forename: Jianxun
authors.identifier: 0000-0002-9734-6176
authors.initials: J
authors.lastname: Song
authors.affiliation: Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033;
authors.forename: Nancy
authors.initials: N
authors.lastname: Olsen
authors.affiliation: Center for Clinic Immunology, Third Hospital, Sun Yat-sen University, Guangzhou 510630, China; Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA 17033; szheng1@hmc.psu.edu anpxu@163.com.
authors.forename: Song Guo
authors.identifier: 0000-0002-5611-4774
authors.initials: SG
authors.lastname: Zheng
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D053804:Granzymes; C509214:Gzmb protein, mouse; C000597315:granzyme A, mouse; C509212:GZMA protein, human