Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation.

Publication Type:

Journal Article

Source:

The Journal of experimental medicine, Volume 207, Issue 4, p.681-8 (2010)

Keywords:

2010, Animals, Antigen Presentation, Antigens, CD31, Antigens, Neoplasm, Autoantigens, Cell Proliferation, Center-Authored Paper, Endothelial Cells, Epitopes, T-Lymphocyte, gene expression, Glutamate Decarboxylase, Histocompatibility Antigens Class I, Human Biology Division, Immune Tolerance, Immunophenotyping, Lymph Nodes, Lymphocyte Activation, MART-1 Antigen, Membrane Glycoproteins, MICE, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Monophenol Monooxygenase, Neoplasm Proteins, Receptors, Antigen, T-Cell, Stromal Cells, T-Lymphocytes, TRANSCRIPTION FACTORS

Abstract:

Peripheral immune tolerance is generally thought to result from cross-presentation of tissue-derived proteins by quiescent tissue-resident dendritic cells to self-reactive T cells that have escaped thymic negative selection, leading to anergy or deletion. Recently, we and others have implicated the lymph node (LN) stroma in mediating CD8 T cell peripheral tolerance. We demonstrate that LN-resident lymphatic endothelial cells express multiple peripheral tissue antigens (PTAs) independent of the autoimmune regulator (Aire). They directly present an epitope derived from one of these, the melanocyte-specific protein tyrosinase, to tyrosinase-specific CD8 T cells, leading to their deletion. We also show that other LN stromal subpopulations express distinct PTAs by mechanisms that vary in their Aire dependence. These results establish lymphatic endothelial cells, and potentially other LN-resident cells, as systemic mediators of peripheral immune tolerance.