Abstract
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.
Highlights
Self-reactive T cells that have escaped negative selection in the thymus are tolerized by both extrinsic and intrinsic mechanisms in the periphery
We demonstrated that deletion of CD8 T cells bearing a transgenic TCR specific for Tyr369, termed ‘FH’, is due to their engagement with Programmed Death Ligand-1 (PD-L1) expressed by radio-resistant lymph nodes (LN) cells and that lymphatic endothelial cells (LEC) express the highest level of PD-L1 among LN stromal cells (LNSC) subpopulations [15]
To address the ability of peripheral tissue LEC to induce tolerance, we examined their expression of PD-L1 and tyrosinase in comparison to LEC isolated from major peripheral and mesenteric LN (LN-LEC)
Summary
Self-reactive T cells that have escaped negative selection in the thymus are tolerized by both extrinsic and intrinsic mechanisms in the periphery. Three groups, including our own, demonstrated that LN stromal cells (LNSC) directly express peripheral tissue antigens (PTA), genes normally restricted to one or a few tissues, and mediate deletion of self-reactive CD8 T cells [5,6,7]. We showed that mice that transgenically express a chimeric HLA-A*0201-based molecule [14], termed ‘AAD’, do not enforce CD8 T cell peripheral tolerance to Tyr369 via negative selection [6]. Tyrosinase-specific CD8 T cells underwent activation and deletion in LN This peripheral tolerance induction was not mediated by conventional DC or Langerhans cells [6] and instead was due to LN-resident LEC (LN-LEC) that directly express tyrosinase mRNA independent of Aire [10]. Our results support a model of systemic peripheral tolerance in which potentially auto-reactive naıve CD8 T cells enter LN, engage self-antigen and PD-L1 expressed on LN-LEC, and undergo deletion
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