Abstract
Lymphatic endothelial cells (LECs) induce peripheral tolerance by direct presentation to CD8 T cells (T(CD8)). We demonstrate that LECs mediate deletion only via programmed cell death-1 (PD-1) ligand 1, despite expressing ligands for the CD160, B- and T-lymphocyte attenuator, and lymphocyte activation gene-3 inhibitory pathways. LECs induce activation and proliferation of T(CD8), but lack of costimulation through 4-1BB leads to rapid high-level expression of PD-1, which in turn inhibits up-regulation of the high-affinity IL-2 receptor that is necessary for T(CD8) survival. Rescue of tyrosinase-specific T(CD8) by interference with PD-1 or provision of costimulation results in autoimmune vitiligo, demonstrating that LECs are significant, albeit suboptimal, antigen-presenting cells. Because LECs express numerous peripheral tissue antigens, lack of costimulation coupled to rapid high-level up-regulation of inhibitory receptors may be generally important in systemic peripheral tolerance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / metabolism
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B7-H1 Antigen / genetics
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B7-H1 Antigen / immunology*
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B7-H1 Antigen / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Endothelial Cells / immunology*
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Endothelial Cells / metabolism
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Immune Tolerance / immunology*
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymphatic Vessels / cytology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Fluorescence
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Monophenol Monooxygenase / genetics
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Monophenol Monooxygenase / immunology
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Monophenol Monooxygenase / metabolism
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology*
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Programmed Cell Death 1 Receptor / metabolism
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Receptors, OX40 / immunology
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Receptors, OX40 / metabolism
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Signal Transduction / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
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Vitiligo / genetics
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Vitiligo / immunology
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Vitiligo / metabolism
Substances
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B7-H1 Antigen
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Cd274 protein, mouse
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell
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Receptors, OX40
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Monophenol Monooxygenase