Liver Sinusoidal Endothelial Cells Tolerize T Cells across MHC Barriers in Mice

Abstract

Although livers transplanted across MHC barriers in mice are normally accepted without recipient immune suppression, the underlying mechanisms remain to be clarified. To identify the cell type that contributes to induction of such a tolerance state, we established a mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Irradiated C57BL/6 (B6) or BALB/c mouse hepatic constituent cells (HCs) and CFSE-labeled B6 splenocytes were cocultured. In allogeneic MHLR, whole HCs did not promote T cell proliferation. When liver sinusoidal endothelial cells (LSECs) were depleted from HC stimulators, allogeneic MHLR resulted in marked proliferation of reactive CD4+ and CD8+ T cells. To test the tolerizing capacity of the LSECs toward alloreactive T cells, B6 splenocytes that had transmigrated through monolayers of B6, BALB/c, or SJL/j LSECs were restimulated with irradiated BALB/c splenocytes. Nonresponsiveness of T cells that had transmigrated through allogeneic BALB/c LSECs and marked proliferation of T cells transmigrated through syngeneic B6 or third-party SJL/j LSECs were observed after the restimulation. Transmigration across the Fas ligand-deficient BALB/c LSECs failed to render CD4+ T cells tolerant. Thus, we demonstrate that Fas ligand expressed on naive LSECs can impart tolerogenic potential upon alloantigen recognition via the direct pathway. This presents a novel relevant mechanism of liver allograft tolerance. In conclusion, LSECs are capable of regulating a polyclonal population of T cells with direct allospecificity, and the Fas/Fas ligand pathway is involved in such LSEC-mediated T cell regulation.

Liver Sinusoidal Endothelial Cells Are a Site of Murine Cytomegalovirus Latency and Reactivation

“…5A), in accordance with the work of Onoe et al (79). Since various MHC-II-negative cell types conditionally express MHC-II upon activation by cytokines, by gamma interferon in particular (106), we surmised that the MHC-II ϩ…”

“…Whereas LSECs were reported to constitutively express MHC-II as well as CD11c, sharing these markers with DCs (reviewed in references 57 and 67), Katz and colleagues presented conflicting results showing low or absent expression of both MHC-II and CD11c by LSECs (50). To make confusion perfect, Onoe and colleagues (79) concluded that murine LSECs express MHC-II but not CD11c. Importantly, as shown above (Fig.…”

Specific gene delivery to liver sinusoidal and artery endothelial cells

“…33 In healthy, adult animals, CD105 is mainly expressed in the distal arteries, distal veins, and capillaries of lung and liver. 22,28,34 The pronounced preference of mCD105-LV particles for liver LSECs is most likely due to a combination of vector particle properties, blood circulation kinetics, and accessibility of the CD105 receptor for the vector particles present in the lumen of the blood vessels. We know from previous work with huCD105-LV, 9 but also other targeting vectors, 12 that transduction efficiency closely correlates with the cell surface density of the targeted receptor.…”

“…However, at least for stellate cells, which have been defined as CD105-positive by biochemical data, 25 the CD105 density must be much lower than that on LSECs, because these can be easily purified from liver using CD105-specific antibodies. 22 In addition, stellate cells are rather inaccessible for systemically applied mCD105-LV because these For personal use only. on June 7, 2019.…”

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines†

“…Transmigrating T cells might rapidly remigrate, receive suppressive signals upon transmigration, 43,44 or subsequently interact with tolerogenic Ito cells. 45 In this respect, endothelial cells from the liver sinusoids seem to possess a special feature in facilitating T cell balance and immune surveillance under homeostatic conditions and presumably even more strongly under inflammatory conditions.…”