Negative CD4+TIM-3 signaling confers resistance against cold preservation damage in mouse liver transplantation

Y. Liu, H. Ji, Y. Zhang, X. D. Shen, F. Gao, T. T. Nguyen, X. Shang, N. Lee, R. W. Busuttil, J. W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Ischemia-reperfusion injury (IRI), an innate immunity-driven local inflammation, remains the major problem in clinical organ transplantation. T cell immunoglobulin and mucin domain (TIM-3)-Galectin-9 (Gal-9) signaling regulates CD4+ Th1 immune responses. Here, we explored TIM-3-Gal-9 function in a clinically relevant murine model of hepatic cold storage and orthotopic liver transplantation (OLT). C57BL/6 livers, preserved for 20h at 4C in UW solution, were transplanted to syngeneic mouse recipients. Up-regulation of TIM-3 on OLT-infiltrating activated CD4+ T cells was observed in the early IRI phase (1h). By 6h of reperfusion, OLTs in recipients treated with a blocking anti-TIM-3 Ab were characterized by: (1) enhanced hepatocellular damage (sALT levels, liver Suzuki's histological score); (2) polarized cell infiltrate towards Th1/Th17-type phenotype; (3) depressed T cell exhaustion markers (PD-1, LAG3); and (4) elevated neutrophil and macrophage infiltration/activation. In parallel studies, adoptive transfer of CD4+ T cells from naïve WT, but not from TIM-3 Tg donors, readily recreated OLT damage in otherwise IR-resistant RAG-/- test recipients. Furthermore, pre-treatment of mice with rGal-9 promoted hepatoprotection against preservation-association liver damage, accompanied by enhanced TIM-3 expression in OLTs. Thus, CD4+ T cell-dependent "negative" TIM-3 costimulation is essential for hepatic homeostasis and resistance against IR stress in OLTs. TIM-3-Gal-9 negative T cell costimulation promotes hepatic homeostasis and cytoprotection against innate immune-driven ischemia reperfusion injury in mouse liver transplants.

Original languageEnglish (US)
Pages (from-to)954-964
Number of pages11
JournalAmerican Journal of Transplantation
Issue number4
StatePublished - Apr 1 2015


  • basic (laboratory) research/science
  • immunobiology
  • innate immunity
  • ischemia reperfusion injury (IRI)
  • liver transplantation/hepatology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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