Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner

Transplantation. 2008 Dec 15;86(11):1492-502. doi: 10.1097/TP.0b013e31818bfd13.


Background: Organ transplantation has been successfully practiced for decades, but the outcome of cell transplantation remains disappointing. This is the case in animal models; liver allografts in mice are spontaneously accepted without requirement of immunosuppression, whereas hepatocyte transplants in the same combination are acutely rejected, apparently resulting from immune attacks because syngeneic hepatocyte transplants survive indefinitely. This suggests that liver nonparenchymal cells play an important role in protecting parenchymal cell from rejection. We have shown that hepatic stellate cells (HpSC), well known to participate in liver repairing and fibrosis, mediate potent immunomodulatory functions through induction of activated T-cell death.

Methods and results: Here, we report that HpSC acquired antigen presenting capacity after activated by interferon-gamma. In contrast to professional antigen-presenting cells dendritic cells that predominantly stimulated CD4+ T cells to generate CD25+ forkhead box P3 (Foxp3)- effector cells, HpSC selectively expanded CD4+ CD25+ Foxp3+ cells in an interleukin-2-dependent manner. These expanded CD4+ CD25+ Foxp3+ cells showed T regulatory cell (Treg) activity in effectively inhibiting T-cell proliferation in responses to anti-CD3 monoclonal antibody or alloantigens in a major histocompatibility complex nonspecific fashion. The Treg cells were expanded from the CD4+ CD25+ population with the help of interleukin-2, independent of B7-H1 and transforming growth factor-beta. Administration of HpSC into allogeneic recipients resulted in expansion of CD4+ CD25+ FoxP3+ cells in vivo.

Conclusion: Liver stromal HpSC acted as nonprofessional antigen-presenting cells, and preferentially expanded CD25+FoxP3+ Treg cells, which may contribute to immune regulation in the liver.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / metabolism
  • CD4 Antigens / biosynthesis*
  • Forkhead Transcription Factors / biosynthesis*
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / biosynthesis*
  • Liver / cytology*
  • Liver / immunology*
  • Liver Transplantation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Stromal Cells / metabolism
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Interferon-gamma