title: Hepatic Stellate Cells Inhibit T Cells through Active TGF-β1 from a Cell Surface-Bound Latent TGF-β1/GARP Complex.
abstract: Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGF-β1, but the detailed mechanisms by which latent TGF-β1 is activated and whether it plays any role in HSC-mediated T cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) is a surface marker of activated regulatory T cells. GARP binds latent TGF-β1 for its activation, which is critical for regulatory T cells to suppress effector T cells; however, it is still unclear whether GARP is present on HSCs and whether it has any impact on HSC function. In this study, we found that TGF-β1(+/-) HSCs, which produce reduced levels of TGF-β1, showed decreased potency in inhibiting T cells. We also found that pharmaceutical or genetic inhibition of the TGF-β1 signaling pathway reduced the T cell-inhibiting activity of HSCs. Additionally, using isolated primary HSCs, we demonstrated that GARP was constitutively expressed on HSCs. Blocking GARP function or knocking down GARP expression significantly impaired the potency of HSCs to suppress the proliferation of and IFN-γ production from activated T cells, suggesting that GARP is important for HSCs to inhibit T cells. These results demonstrate the unexpected presence of GARP on HSCs and its significance in regard to the ability of HSCs to activate latent TGF-β1 and thereby inhibit T cells. Our study reveals a new mechanism for HSC-mediated immune regulation and potentially for other conditions, such as liver fibrosis, that involve HSC-secreted TGF-β1.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106; and.
authors.forename: Byung-Gyu
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Shiguang
authors.initials: S
authors.lastname: Qian
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.affiliation: Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; linf2@ccf.org.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D055166:Hepatic Stellate Cells / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008099:Liver / Q000276:immunology; D008103:Liver Cirrhosis / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma