title: Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction.
abstract: Lymphatic endothelial cells (LECs) directly express peripheral tissue antigens and induce CD8 T-cell deletional tolerance. LECs express MHC-II molecules, suggesting they might also tolerize CD4 T cells. We demonstrate that when β-galactosidase (β-gal) is expressed in LECs, β-gal-specific CD8 T cells undergo deletion via the PD-1/PD-L1 and LAG-3/MHC-II pathways. In contrast, LECs do not present endogenous β-gal in the context of MHC-II molecules to β-gal-specific CD4 T cells. Lack of presentation is independent of antigen localization, as membrane-bound haemagglutinin and I-Eα are also not presented by MHC-II molecules. LECs express invariant chain and cathepsin L, but not H2-M, suggesting that they cannot load endogenous antigenic peptides onto MHC-II molecules. Importantly, LECs transfer β-gal to dendritic cells, which subsequently present it to induce CD4 T-cell anergy. Therefore, LECs serve as an antigen reservoir for CD4 T-cell tolerance, and MHC-II molecules on LECs are used to induce CD8 T-cell tolerance via LAG-3.
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Sherin J
authors: SJ
authors: Rouhani
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Jacob D
authors: JD
authors: Eccles
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Priscila
authors: P
authors: Riccardi
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: J David
authors: JD
authors: Peske
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Eric F
authors: EF
authors: Tewalt
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Jarish N
authors: JN
authors: Cohen
authors: 1] INSERM, Unité 1043, F-31300 Toulouse, France [2] Centre National de la Recherche Scientifique, Unité 5282, F-31300 Toulouse, France [3] Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse, Université Paul Sabatier, F-31300 Toulouse, France [4] Département d'Immunologie, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, F-31300 Toulouse, France.
authors: Roland
authors: R
authors: Liblau
authors: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjoldsv. 20, 751 85 Uppsala, Sweden.
authors: Taija
authors: T
authors: Mäkinen
authors: Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Victor H
authors: VH
authors: Engelhard
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D000941:Antigens / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D056668:Cathepsin L / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D015870:Gene Expression; D006388:Hemagglutinins / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061166:Peripheral Tolerance / Q000235:genetics*; D061251:Primary Cell Culture; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006388:Hemagglutinins; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C045084:invariant chain; D001616:beta-Galactosidase; C534281:CTSL protein, human; D056668:Cathepsin L; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse