Factors Controlling the Tolerogenic Phenotype of Lymphatic Endothelial Cells.

The Journal of Immunology(2017)

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摘要
Abstract The prevailing model of peripheral tolerance necessitates tissue-resident dendritic cells migrating to lymph nodes and cross presenting self-antigen to T cells, resulting in their deletion or anergy. Our lab has identified a novel mechanism of peripheral tolerance involving a subset of lymph node stromal cells called lymphatic endothelial cells (LEC). LEC in the lymph node induce peripheral tolerance by presenting epitopes derived from peripheral tissue antigens (PTAs) in conjunction with expression of PD-L1, leading to CD8 T cell deletion. However, PTAs and PD-L1 are not expressed on LEC in the colon or diaphragm. We performed RNAseq analysis on LEC from lymph node and diaphragm to identify differences in expression of transcription factors that might control expression of PD-L1 and PTA. We found that Spi-B is the most differentially expressed transcription factor in the lymph node compared to the diaphragm, with a fold change of over 500. Spi-B has been implicated in the development and function of medullary thymic epithelial cells, a key cell type in central tolerance. Lymph node LEC harvested from Spi-B deficient mice have a significant shift in markers associated with LEC tolerogenicity. Expression levels of PD-L1, ICAM-1, MAdCAM-1, and LTbR delineate different lymph node LEC subpopulations that vary in their ability to express PTAs and tolerize CD8 T cells. LEC from Spi-B deficient mice have decreased MAdCAM-1 expression and increased LTbR and ICAM-1 expression suggesting a population shift of non-tolerogenic lymph node LEC to tolerogenic lymph node LEC. This data suggests Spi-B may be involved in a negative feedback mechanism to limit the number of tolerogenic LEC during development.
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