Interaction between lymph and liver cells may affect immune response

The results of this study appear in the November 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc., Hepatology is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/hepatology.

The liver possesses an unusual ability to stimulate immune tolerance, possibly due to its distinctive architecture that allows T cells normally activated in the lymph system to become activated by liver cells. Normally, endothelial cells that line blood vessels form a physical barrier that prevents naïve (unactivated) T cells from accessing surrounding tissue; these cells must typically be activated by specialized cells known as professional antigen presenting cells (APCs) before they are able to migrate across the endothelium and interact with organ cells. Recent studies have shown that the liver is an exception in that liver cells may be able to act as APCs, activating T cells independently of the lymph system, a process which makes them less efficient. However, the question remains as to how T cells can cross the endothelial barrier to interact with liver cells.

A collaborative work between Alessandra Warren and David Le Couteur of the Centre for Education and Research on Ageing (CERA), Concord RG Hospital and Patrick Bertolino of the Centenary Institute, University of Sydney, Australia, has led to the first study investigating the interactions between lymphocytes (T cells), liver sinusoidal endothelial cells (LSECs) and hepatocytes (liver cells) using electron microscopy. LSECs are highly specialized endothelial cells that line the walls of hepatic sinusoid cells (gossamer-like structures that form the rich capillary network of the liver) and are perforated by fenestrations, or openings. The researchers hypothesized that the fenestrations could provide a portal through which liver cells and T cells could interact or that the interaction could take place across gaps between LSECs.

The study was conducted using mice whose livers had been injected with lymphocytes. The mouse livers were examined with two types of electron microscopy. Analysis of the images showed a large number of intrahepatic lymphocytes (IHLs) that had extensions similar to the dimensions of the fenestrations of the LSECs. These extensions were seen within the fenestrations and were observed to be in contact with minute projections on liver cells (hepatocyte microvilli). There were no observable gaps between LSECs and hepatocyte microvilli did not seem to interact with circulating lymphocytes. Further investigation showed that naïve T cells displayed the same extensions as IHLs and were also able to interact with liver cells through LSEC fenestrations. The authors propose the term “trans-endothelial hepatocyte-lymphocyte interactions” (TEHLI) to describe these interactions.

The discovery of TEHLI is the first demonstration by electron microscopy of the interaction between naïve T cells and liver cells in a living organism, which shows that the liver is an exception to the rule that T cells need to be activated by professional APCs in order to cross the endothelial barrier, and that hepatocytes can function as APCs. In fact, this T cell activation in the liver during early hepatitis C infection may contribute to the impaired immune response seen in chronic hepatitis C.

“As well as providing insight into the normal immune system, our observations might have implications for liver conditions associated with altered LSEC morphology and in particular those conditions associated with loss of fenestrations such as cirrhosis and old age,” the authors conclude. “We have shown [in previous studies] that old age is associated with dramatic reductions in the fenestrations of LSECs therefore the altered immune responses of older people might in part be mechanistically linked to reduced opportunity for TEHLI in old age.”

In an accompanying editorial in the same issue, Erin F. McAvoy and Paul Kubes of the University of Calgary in Alberta, Canada note that although the authors did not observe any interaction between hepatocyte microvilli and circulating lymphocytes, it is possible that this type of transient interaction is difficult to capture using electron microscopy. They suggest that the hepatocyte microvilli could function as a rapid screen for circulating lymphocytes, which might then decide to adhere and start the TEHLI process. “The notion that naïve T lymphocytes are capable of directly interacting with hepatocytes contradicts the dogma that naïve T cells cannot gain access to peripheral non-lymphoid tissues,” the authors state, adding that the study furthers the notion that liver cells may be involved in hepatic immune tolerance. “Like any good study,” they conclude, “the work of Warren et al., answers important questions but also raises some new and intriguing areas for further exploration.”