Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7771
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Funding
- NCI Cancer Center [5 P30 CA044579]
- USPHS [AI068836, AI099033, AI109250, AI07496]
- American Cancer Society [GM007267, CA009109, PF-10-156-01-LIB]
- Ministry of Education of Brazil, Brasilia-DF [70.040-020]
- Cancer Research UK
- CAPES Foundation
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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 beta-galactosidase (beta-gal) is expressed in LECs, beta-gal-specific CD8 Tcells undergo deletion via the PD-1/PD-L1 and LAG-3/MHC-II pathways. In contrast, LECs do not present endogenous b-gal in the context of MHC-II molecules to b-gal-specific CD4 T cells. Lack of presentation is independent of antigen localization, as membrane-bound haemagglutinin and I-Ea 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 b-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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