T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

Abstract

The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node-activated T cells, liver-activated T cells are shortlived, a mechanism that might contribute to the "liver tolerance effect." Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8 ؉ T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that naïve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating naïve CD8 ؉ T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion, this study has identified, at the ultrastructural level, a unique type of interaction between naïve T lymphocytes and liver parenchymal cells in vivo. These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.

Drug-induced liver injury in older adults

“…Age-related defenestration of the liver sinusoid affects the hepatic disposition of lipoproteins [Hilmer et al 2005a;Le Couteur et al 2002] and medications [Mitchell et al 2010b] and may play a role in autoimmune disease in older people by impeding the interactions between naive T lymphocytes and hepatocytes that are thought to induce immunotolerance [Warren et al 2006]. Hepatic glutathione content decreases with age in animals [Wang et al 2003;Stio et al 1994] and humans [Lang et al 1992].…”

“…Physiological changes associated with ageing and frailty that can have an impact on the pharmacokinetics and pharmacodynamics of drugs. Adapted from Mitchell et al [2009a] and references [Hilmer and Ford, 2009;Hilmer, 2008;López-Lluch et al 2008;Hilmer et al 2007aHilmer et al , 2005aWarren et al 2006;Wang et al 2003;Le Couteur et al 2002, 2001Hämmerlein et al 1998;Klotz, 1998;Kinirons et al 1997;Stio et al 1994;Lang et al 1992]. [Schenker et al 1999].…”

Inefficient fusion due to a lack of attachment receptor/co-receptor restricts productive human immunodeficiency virus type 1 infection in human hepatoma Huh7.5 cells

“…Such a mechanism based on physical transfer of a piece of membrane bearing proteins during cell-to-cell contact is also called trogocytosis and is known to be a mechanism of intercellular communication (Joly & Hudrisier, 2003;Niu et al, 2009). Knowing that close direct interactions between CD4-expressing T-cells and hepatocytes can occur in the liver (Warren et al, 2006), it can be postulated that a transfer of plasma membrane fragments containing CD4 can enhance susceptibility of hepatocytes to HIV-1 infection. Moreover, the intercellular exchanges of intact membrane patches can also take place through another intercellular communication mechanism relying on membrane vesicles either directly shed from the surface membranes or secreted from the endosomal compartment of a donor cell (Ratajczak et al, 2006).…”

Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells

“…Notably, they also function as APCs contributing to T cell activation and immune regulation in the liver. HCs interact and establish cell-cell contact with T lymphocytes through fenestrations in liver sinusoidal endothelial cells (4). HCs constitutively express MHC class I molecules, and MHC class II expression has been demonstrated in HCs in response to IFN-g exposure or in patients with various forms of chronic liver disease (5).…”