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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen Presentation / genetics*
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Antigens / genetics
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Antigens / immunology
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Antigens, CD / genetics
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Antigens, CD / immunology*
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / immunology
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B7-H1 Antigen / genetics
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B7-H1 Antigen / immunology
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Bone Marrow Cells / cytology
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Bone Marrow Cells / immunology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology
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Cathepsin L / genetics
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Cathepsin L / immunology
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Clonal Anergy / genetics
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Endothelial Cells / cytology
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Endothelial Cells / immunology*
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Gene Expression
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Hemagglutinins / genetics
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Hemagglutinins / immunology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology
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Lymphocyte Activation Gene 3 Protein
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Peripheral Tolerance / genetics*
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Primary Cell Culture
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology
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Signal Transduction
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beta-Galactosidase / genetics
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beta-Galactosidase / immunology
Substances
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Antigens
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Antigens, CD
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Antigens, Differentiation, B-Lymphocyte
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B7-H1 Antigen
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Cd274 protein, mouse
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Hemagglutinins
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Histocompatibility Antigens Class II
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I-E-antigen
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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invariant chain
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beta-Galactosidase
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CTSL protein, human
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Cathepsin L
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Lymphocyte Activation Gene 3 Protein
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Lag3 protein, mouse