Hepatic Stellate Cells Preferentially Expand Allogeneic CD4+ CD25+ FoxP3+ Regulatory T Cells in an IL-2-Dependent Manner
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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.
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HSCs amplify populations of tolerizing immune cells including FoxP3+ regulatory T cells (via retinoic acid and TGFβ signaling) and myeloid-derived suppressor cells.
“They also amplify populations of tolerizing immune cells including FoxP3+ regulatory T cells (via retinoic acid and TGFβ signaling) (41, 43, 50, 51) and myeloid-derived suppressor cells (52).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [50]
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- Authors
- Jiang, G., Yang, H.-R., Wang, L., Wildey, G. M., Fung, J., Qian, S., & Lu, L.
- Affiliations
- Cleveland Clinic (US)
- Corresponding author
- Qian, Shiguang
- Venue
- Transplantation
- Published
- 2008-12-15
- Volume
- 86
- Issue
- 11
- Pages
- 1492-1502
- ISSN
- 0041-1337 (ISSN-L)
- PMC
- PMC2888269
- OpenAlex
- W2027257408
- Cited by
- 96
- References
- 38
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 6 · 2020: 8 · 2019: 4 · 2018: 1 · 2017: 6 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 7 · 2012: 6
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Transplantation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Johns Hopkins University
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058316, DK58316)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- hepatic stellate cells, regulatory T cells, Foxp3, interleukin-2, antigen presentation, interferon-gamma, liver transplantation, hepatocyte transplantation, allograft rejection, immune tolerance, Treg expansion, immunomodulation
- MeSH terms
- Animals, Antigen-Presenting Cells, Interferon-gamma, Interleukin-2, Liver, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, CD4 Antigens, Liver Transplantation, Stromal Cells, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit
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