title: Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells.
abstract: Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8(+) T cells. This cross-presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum-golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8(+) T cells. Finally, Ag-specific CD8(+) T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8(+) T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node-resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags.
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirosue
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Efthymia
authors.initials: E
authors.lastname: Vokali
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Vidya R
authors.initials: VR
authors.lastname: Raghavan
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Marcela
authors.initials: M
authors.lastname: Rincon-Restrepo
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Lund
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Patricia
authors.initials: P
authors.lastname: Corthésy-Henrioud
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Francesca
authors.initials: F
authors.lastname: Capotosti
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich (ETHZ), Zürich, Switzerland;
authors.forename: Cornelia
authors.initials: C
authors.lastname: Halin Winter
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, Centre Médical Universitaire, Université de Genève, Geneva, Switzerland; and.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hugues
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland melody.swartz@epfl.ch.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002461:Cell Line, Transformed; D003429:Cross Reactions / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000941:Antigens; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2