Journal Article

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

Mäkinen, Taija, Liblau, Roland, Tewalt, Eric F., Eccles, Jacob D., Peske, J. David, Riccardi, Priscila, Cohen, Jarish N., Engelhard, Victor H., Rouhani, Sherin J.

2015

Overview

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. Lymphatic endothelial cells (LECs) induce peripheral tolerance of CD8 T cells. Here the authors show that LECs cannot directly tolerize CD4 T cells as they lack the machinery for loading the antigenic peptide to MHC-II; instead, LECs pass these antigens to dendritic cells that induce CD4 tolerance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 13/106 / 13/31 / 14/63 / 38/77 / 631/250/1617 / 631/250/2152/1566/20 / 631/250/2152/569 / Animals / Antigen Presentation - genetics / Antigens - genetics / Antigens - immunology / Antigens, CD - genetics / Antigens, CD - immunology / Antigens, Differentiation, B-Lymphocyte - genetics / Antigens, Differentiation, B-Lymphocyte - immunology / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / beta-Galactosidase - genetics / beta-Galactosidase - immunology / Bone Marrow Cells - cytology / Bone Marrow Cells - immunology / Cathepsin L - genetics / Cathepsin L - immunology / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - immunology / Clonal Anergy - genetics / Dendritic Cells - cytology / Dendritic Cells - immunology / Endothelial Cells - cytology / Endothelial Cells - immunology / Gene Expression / Hemagglutinins - genetics / Hemagglutinins - immunology / Histocompatibility Antigens Class II - genetics / Histocompatibility Antigens Class II - immunology / Humanities and Social Sciences / Mice / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Peptides / Peripheral Tolerance - genetics / Primary Cell Culture / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Science / Science (multidisciplinary) / Signal Transduction