Mechanistic insights into immunomodulation by hepatic stellate cells in mice: A critical role of interferon‐γ signaling

• Published in: Hepatology (Baltimore, Md.) Vol. 50; no. 6; pp. 1981 - 1991
• Main Authors: Yang, Horng‐Ren, Chou, Hong‐Shuie, Gu, Xiaodong, Wang, Lianfu, Brown, Kathleen E., Fung, John J., Lu, Lina, Qian, Shiguang
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-12-2009; Wiley
• Subjects: Animals; Apoptosis; B7-1 Antigen - genetics; B7-1 Antigen - physiology; B7-H1 Antigen; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Forkhead Transcription Factors - physiology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic Stellate Cells - immunology; Interferon gamma Receptor; Interferon-gamma - physiology; Islets of Langerhans Transplantation; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred Strains; Peptides - genetics; Peptides - physiology; Receptors, Interferon - physiology; Signal Transduction - physiology; T-Lymphocytes, Regulatory - physiology; Spider cell; Vertebrata; Mammalia; Mouse; Immunomodulation; Animal; Liver; Rodentia; Gastroenterology; Gamma interferon
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.23202

The liver is considered to be an immune‐privileged organ that favors the induction of tolerance. The underlying mechanisms are not completely understood. Interestingly, liver transplants are spontaneously accepted in several animal models, but hepatocyte transplants are acutely rejected, suggesting that liver nonparenchymal cells may effectively protect the parenchymal cells from immune attack. We have shown the profound T cell inhibitory activity of hepatic stellate cells (HSCs). Thus, cotransplantation with HSCs effectively protects islet allografts from rejection in mice. In this study, using T cell receptor transgenic and gene knockout approaches, we provided definitive evidence that HSCs protected cotransplanted islet allografts by exerting comprehensive inhibitory effects on T cells, including apoptotic death in graft‐infiltrating antigen‐specific effector T cells and marked expansion of CD4+ Forkhead box protein (Foxp)3+ T regulatory (Treg) cells. All these effects required an intact interferon‐γ (IFN‐γ) signaling in HSCs, demonstrated by using HSCs isolated from IFN‐γ receptor 1 knockout mice. B7‐H1 expression on HSCs, a product molecule of IFN‐γ signaling, was responsible for induction of T cells apoptosis, but had no effect on expansion of Treg cells, suggesting that undetermined effector molecules produced by IFN‐γ signaling is involved in this process. Conclusion: Upon inflammatory stimulation, specific organ stromal cells (such as HSCs in the liver) demonstrate potent immune regulatory activity. Understanding of the mechanisms involved may lead to development of novel strategies for clinical applications in transplantation and autoimmune diseases. (HEPATOLOGY 2009.)