title: Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury.
abstract: OBJECTIVE
  By binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation.
  
  
  METHODS
  We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT).
  
  
  RESULTS
  Orthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells.
  
  
  CONCLUSIONS
  Harnessing TIM-3/Gal-9 signalling at the T cell-hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yuanxing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Haofeng
authors.initials: H
authors.lastname: Ji
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Xiuda
authors.initials: X
authors.lastname: Shen
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: He
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Gabriella A
authors.initials: GA
authors.lastname: Li
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA. Electronic address: jkupiec@mednet.ucla.edu.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D004195:Disease Models, Animal; D037161:Galectins / Q000276:immunology*; D005978:Glutathione; D000072597:Hepatitis A Virus Cellular Receptor 2; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007328:Insulin; D016031:Liver Transplantation / Q000009:adverse effects; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D009926:Organ Preservation; D019188:Organ Preservation Solutions; D011887:Raffinose; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology*; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007328:Insulin; D019188:Organ Preservation Solutions; D011991:Receptors, Virus; C055206:University of Wisconsin-lactobionate solution; C508186:galectin 9, mouse; D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose
keywords: Galectin-9; Innate immunity; Ischemia-reperfusion injury; Liver; Orthotopic liver transplantation; TIM-3