title: Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells.
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.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Tewalt
authors.forename: Jarish N
authors.initials: JN
authors.lastname: Cohen
authors.forename: Sherin J
authors.initials: SJ
authors.lastname: Rouhani
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidi
authors.forename: Hui
authors.initials: H
authors.lastname: Qiao
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Fahl
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Bender
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Tung
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Vella
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Adler
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Victor H
authors.initials: VH
authors.lastname: Engelhard
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D042601:Lymphatic Vessels / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology / Q000378:metabolism; D014820:Vitiligo / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014442:Monophenol Monooxygenase