Hepatic Stellate Cells Function as Regulatory Bystanders
Open accessAbstract
Regulatory T cells (Tregs) contribute significantly to the tolerogenic nature of the liver. The mechanisms, however, underlying liver-associated Treg induction are still elusive. We recently identified the vitamin A metabolite, retinoic acid (RA), as a key controller that promotes TGF-β–dependent Foxp3+ Treg induction but inhibits TGF-β–driven Th17 differentiation. To investigate whether the RA producing hepatic stellate cells (HSC) are part of the liver tolerance mechanism, we investigated the ability of HSC to function as regulatory APC. Different from previous reports, we found that highly purified HSC did not express costimulatory molecules and only upregulated MHC class II after in vitro culture in the presence of exogenous IFN-γ. Consistent with an insufficient APC function, HSC failed to stimulate naive OT-II TCR transgenic CD4+T cells and only moderately stimulated α-galactosylceramide–primed invariant NKT cells. In contrast, HSC functioned as regulatory bystanders and promoted enhanced Foxp3 induction by OT-II TCR transgenic T cells primed by spleen dendritic cells, whereas they greatly inhibited the Th17 differentiation. Furthermore, the regulatory bystander capacity of the HSC was completely dependent on their ability to produce RA. Our data thus suggest that HSC can function as regulatory bystanders, and therefore, by promoting Tregs and suppressing Th17 differentiation, they might represent key players in the mechanism that drives liver-induced tolerance.
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HSCs can acquire some features of antigen presenting cells, including expression of MHC class I and II and T cell-activating costimulatory molecules such as CD86, although more recent evidence suggests HSCs have limited APC capabilities in vivo.
“HSCs can acquire some features of antigen presenting cells (APCs), including expression of major histocompatibility complexes (MHC) class I and II, and T cell-activating costimulatory molecules such as CD86 (40–42), although more recent evidence suggests HSCs have limited APC capabilities in vivo (43).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [43]
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 [43]
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- Authors
- Ichikawa, S., Mucida, D., Tyznik, A. J., Kronenberg, M., & Cheroutre, H.
- Affiliations
- La Jolla Institute for Immunology (US)
- Rockefeller University (US)
- Corresponding author
- Ichikawa, Shintaro
- Kronenberg, Mitchell
- Cheroutre, Hilde
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-05
- Volume
- 186
- Issue
- 10
- Pages
- 5549-5555
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3132534
- OpenAlex
- W2135953421
- Cited by
- 141
- References
- 42
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 10 · 2023: 7 · 2022: 7 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 12 · 2016: 18 · 2015: 16 · 2014: 11 · 2013: 16 · 2012: 8
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Crohn's and Colitis Foundation
- National Institutes of Health (5r01ai050265-13)
- National Institute of Allergy and Infectious Diseases (R01-AI050265)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- hepatic stellate cells, regulatory T cells, retinoic acid, liver tolerance, Th17 cell differentiation, Foxp3 induction, antigen-presenting cells, MHC class II upregulation, invariant NKT cells, TGF-beta signaling, OT-II T cells, alpha-galactosylceramide
- MeSH terms
- Animals, Cells, Cultured, Dendritic Cells, Flow Cytometry, Galactosylceramides, Genes, MHC Class II, Interferon-gamma, Killer Cells, Natural, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Antigen, T-Cell, Tretinoin, CD4-Positive T-Lymphocytes, Polymerase Chain Reaction, Mice, Forkhead Transcription Factors, Hepatic Stellate Cells, Th17 Cells
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