title: Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment.
abstract: Peripheral self-tolerance eliminates lymphocytes specific for tissue-specific antigens not encountered in the thymus. Recently, we demonstrated that lymphatic endothelial cells in mice directly express peripheral tissue antigens, including tyrosinase, and induce deletion of specific CD8 T cells via Programmed Death Ligand-1 (PD-L1). Here, we demonstrate that high-level expression of peripheral tissue antigens and PD-L1 is confined to lymphatic endothelial cells in lymph nodes, as opposed to tissue (diaphragm and colon) lymphatics. Lymphatic endothelial cells in the lymph node medullary sinus express the highest levels of peripheral tissue antigens and PD-L1, and are the only subpopulation that expresses tyrosinase epitope. The representation of lymphatic endothelial cells in the medullary sinus expressing high-level PD-L1, which is necessary for normal CD8 T cell deletion kinetics, is controlled by lymphotoxin-β receptor signaling and B cells. Lymphatic endothelial cells from neonatal mice do not express high-level PD-L1 or present tyrosinase epitope. This work uncovers a critical role for the lymph node microenvironment in endowing lymphatic endothelial cells with potent tolerogenic properties.
authors: Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Jarish N
authors: JN
authors: Cohen
authors: Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Eric F
authors: EF
authors: Tewalt
authors: Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Sherin J
authors: SJ
authors: Rouhani
authors: Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Erica L
authors: EL
authors: Buonomo
authors: Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Amber N
authors: AN
authors: Bruce
authors: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Xiaojiang
authors: X
authors: Xu
authors: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Stefan
authors: S
authors: Bekiranov
authors: Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
authors: Yang-Xin
authors: YX
authors: Fu
authors: Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors: Victor H
authors: VH
authors: Engelhard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D060833:Cellular Microenvironment / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism*; D004729:Endothelium, Lymphatic / Q000378:metabolism*; D007108:Immune Tolerance; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism*; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009088:Mucoproteins; D010641:Phenotype; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D015815:Cell Adhesion Molecules; D053259:Lymphotoxin beta Receptor; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D014442:Monophenol Monooxygenase