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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.

Author information

1
Carter Immunology Center, Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
2
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.
3
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjoldsv. 20, 751 85 Uppsala, Sweden.

Abstract

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.

PMID:
25857745
PMCID:
PMC4403767
DOI:
10.1038/ncomms7771
[Indexed for MEDLINE]
Free PMC Article

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