Mechanistic insights into immunomodulation by hepatic stellate cells in mice: a critical role of interferon-gamma signaling.
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-gamma (IFN-gamma) signaling in HSCs, demonstrated by using HSCs isolated from IFN-gamma receptor 1 knockout mice. B7-H1 expression on HSCs, a product molecule of IFN-gamma 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-gamma signaling is involved in this process.


CONCLUSIONS
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.
Yang
Horng-Ren
HR
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Chou
Hong-Shuie
HS
Gu
Xiaodong
X
Wang
Lianfu
L
Brown
Kathleen E
KE
Fung
John J
JJ
Lu
Lina
L
Qian
Shiguang
S
D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000235:genetics / Q000502:physiology; D017471:Receptors, Interferon / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D000096743:Interferon gamma Receptor
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D008562:Membrane Glycoproteins; D010455:Peptides; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C498919:Cd274 protein, mouse; C498833:Foxp3 protein, mouse