| Autor: |
Cohen JN; Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Tewalt EF; Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Rouhani SJ; Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Buonomo EL; Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Bruce AN; Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Xu X; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Bekiranov S; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America., Fu YX; Department of Pathology, University of Chicago, Chicago, Illinois, United States of America., Engelhard VH; Department of Microbiology, Immunology, and Cancer Biology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America. |
| Abstrakt: |
Peripheral self-tolerance eliminates lymphocytes specific for tissue-specific antigens not encountered in the thymus. Recently, we demonstrated that lymphatic endothelial cells in mice directly express peripheral tissue antigens, including tyrosinase, and induce deletion of specific CD8 T cells via Programmed Death Ligand-1 (PD-L1). Here, we demonstrate that high-level expression of peripheral tissue antigens and PD-L1 is confined to lymphatic endothelial cells in lymph nodes, as opposed to tissue (diaphragm and colon) lymphatics. Lymphatic endothelial cells in the lymph node medullary sinus express the highest levels of peripheral tissue antigens and PD-L1, and are the only subpopulation that expresses tyrosinase epitope. The representation of lymphatic endothelial cells in the medullary sinus expressing high-level PD-L1, which is necessary for normal CD8 T cell deletion kinetics, is controlled by lymphotoxin-β receptor signaling and B cells. Lymphatic endothelial cells from neonatal mice do not express high-level PD-L1 or present tyrosinase epitope. This work uncovers a critical role for the lymph node microenvironment in endowing lymphatic endothelial cells with potent tolerogenic properties. |
