Lymphatic endothelial cells Sample Clauses

Lymphatic endothelial cells. With the relatively recent discovery of specific markers for LECs in humans and mice such as LYVE-1 (134), podoplanin (193), and VEGFR3 (194); research in this field has grown. Pure populations of LEC can be isolated from a variety of tissue types and pathologies, allowing elucidation of their functionality, in particular their ability to regulate the adaptive immune response (reviewed in (122)). LECs express MHC class I and can present self-antigen to CD8+ T cells for tolerance induction in non-transplant models (195, 196). Lymph node LEC (LN-LEC) express high levels of the co-inhibitory molecule PDL1, and low levels of the classic co-stimulatory molecules CD80 and CD86. The absence of sufficient co-stimulatory signals leads to upregulation of PD1 on CD8+ T cells and subsequent engagement with PDL1 on LEC in the lymph node leading to CD8+ T cell deletion (196). Therefore, LECs contribute to peripheral tolerance by inducing CD8+ T cell deletion via PDL1. Lymph nodes have been found to be an important site for self-tolerance induction, with many lymph node stromal cell types (including LEC) having the ability to directly present self-antigen and induce CD8+ T cell deletion (197). In a melanoma model, tumour expression of VEGF-C was found to promote immune tolerance of tumours by the host. Local tumour-specific CD8+ T cells were deleted, and LN-LECs were able to cross-present tumour antigen, and drive CD8+ T cell proliferation and apoptosis ex vivo (198). LEC-mediated induction of CD4+ T cell tolerance is less well characterised, although some progress has been made. It appears that CD4+ T cell self-tolerance induction is mediated by interaction with DCs. MHC class II expression by LECs is under the control of the IFN-γ inducible promoter IV, therefore its expression is minimal in steady-state conditions. Xxxxxx et al. found that LECs acquire antigenic peptide-MHC class II complexes from DCs as a result of cell-cell contact and exosomes (199). These acquired complexes are presented to cognate CD4+ T cells, resulting in CD4+ T cell dysfunction and resistance to further stimulation. Others have found that LEC can act as antigen reservoirs for DCs (200). Although LECs do express MHC class II (albeit minimally), they cannot load endogenous peptides onto MHC II molecules due to the lack of H2-M. Therefore, they transfer endogenous peptides to DCs, which are then loaded onto MHC class II and presented to CD4+ T cells for tolerance induction. It appears that endoge...