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Nat Commun. 2015 Apr 10;6:6771. doi: 10.1038/ncomms7771.

Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction.

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Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
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.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjoldsv. 20, 751 85 Uppsala, Sweden.


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.

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