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

Sherin J. Rouhani, Jacob D. Eccles, Priscila Riccardi, J. David Peske, Eric F. Tewalt, Jarish N. Cohen, Roland Liblau, Taija Mäkinen and Victor H. Engelhard ()
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Sherin J. Rouhani: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine
Jacob D. Eccles: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine
Priscila Riccardi: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine
J. David Peske: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine
Eric F. Tewalt: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine
Jarish N. Cohen: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine
Roland Liblau: INSERM
Taija Mäkinen: Genetics and Pathology, Rudbeck Laboratory, Uppsala University
Victor H. Engelhard: Carter Immunology Center, Immunology and Cancer Biology, University of Virginia School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7771

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