PD-L1 is induced in hepatocytes by viral infection and by interferon-a and -c and mediates T cell apoptosis Marcus Mu ¨ hlbauer 1,] , Martin Fleck 1,] , Christian Schu ¨tz 1 , Thomas Weiss 2 , Matthias Froh 1 , Christian Blank 3 , Ju ¨ rgen Scho ¨ lmerich 1 , Claus Hellerbrand 1, * 1 Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany 2 Department of Surgery, University of Regensburg, D-93042 Regensburg, Germany 3 Division of Hematology and Oncology, University of Regensburg, D-93042 Regensburg, Germany See Editorial, pages 468–472 Background/ Aims: B7-H1 (PD-L1) is a B7-family member that binds to programmed death-1 (PD-1). Recently, defi- ciency of PD-L1 has been demonstrated to result in accelerated hepatocyte damage in experimental autoimmune hepatitis, and PD-L1 was suggested to play a critical role in regulating T cell homeostasis. Absence of PD-1 enhanced proliferation of T cells in adenovirus-infected livers and resulted in a rapid clearance of the virus. Here, we aimed to get more insight into hepatic PD-L1 expression, regulation and function. Methods: PD-L1 expression was analyzed by quantitative PCR and FACS-analysis in primary human liver cells and hepatoma cells. Furthermore, coculture experiments with primary human T cells or Jurkat T cells were established. Results: In addition to nonparenchymal liver cells, also hepatocytes constitutively expressed low levels of PD-L1. PD-L1 expression in hepatocytes was strongly enhanced by activated T cells and viral infection, and markedly augmented by fur- ther stimulation with type I or type II interferons. Moreover, PD-L1 expression on hepatocytes induced apoptosis in T cells. Conclusions: Our results suggest a novel bidirectional interaction between hepatocytes and lymphocytes modulated by PD-L1 expression in hepatocytes, which may contribute to the unique immunological properties of the liver. Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: PD-L1; B7-H1; PD-1; Apoptosis; Liver; Hepatocytes; Tolerance 1. Introduction The liver is constantly exposed to bacterial products and food-derived antigens. These antigens and microbi- ologically derived molecules provide a unique hepatic microenvironment and require unique immunological properties of the liver which often induces peripheral tolerance rather than immunity [1,2]. Hepatic tolerance may also contribute to the common ineffectiveness of immune responses against hepatitis viruses such as HBV and HCV which often results in chronic persis- tence of viral infection [3]. The molecular mechanisms underlying these observations have not yet been eluci- dated. However, it has been hypothesized that there are unusual interactions within the hepatic milieu and immune cells [1]. B7-like molecules and their cognate receptors consti- tute important costimulatory pathways that control and fine-tune immune responses. In recent years, an array of new members of the B7 family have been identified, 0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.05.007 Received 17 March 2006; received in revised form 26 April 2006; accepted 9 May 2006; available online 16 June 2006 * Corresponding author. Tel.: +49 941 944 7155; fax: +49 941 944 7154. E-mail address: claus.hellerbrand@klinik.uni-regensburg.de (C. Hellerbrand). ] Both authors contributed equally to this work. Abbreviations: PD-1, Programmed death-1; PD-L1, Programmed death-ligand-1; HSC, Hepatic stellate cells; PHH, Primary human hepatocytes. www.elsevier.com/locate/jhep Journal of Hepatology 45 (2006) 520–528