Connecting Liver and Gut: Murine Liver Sinusoidal Endothelium Induces Gut Tropism of CD4+ T Cells via Retinoic Acid
Open accessAbstract
Gut-activated T cells migrating into the liver can cause extraintestinal manifestations of inflammatory bowel disease. T cells acquire a gut-homing phenotype dependent on retinoic acid (RA) provided by intestinal dendritic cells (DC). We investigated whether liver antigen-presenting cells can induce gut tropism supporting an enterohepatic lymphocyte circulation. Priming of CD4+ T cells by liver sinusoidal endothelial cells (LSEC) supported migration into gut and gut-associated lymphoid tissue. As observed for T cells primed by intestinal DCs, this gut tropism depended on α4β7 integrin and CC chemokine receptor 9 (CCR9) expression by LSEC-primed CD4+ T cells. The induction of gut-homing molecules was mediated by RA, a derivate of vitamin A that is stored in large amounts within the liver. LSECs expressed functional retinal dehydrogenases and could convert vitamin A to RA. Conversely, the lack of signaling via the RA receptor prevented the expression of α4β7 integrin and CCR9 on LSEC-primed CD4+ T cells, consequently reducing their in vivo migration to the intestine. Other liver antigen-presenting cells failed to support high expression of α4β7 integrin on CD4+ T cells, thus, the potential to induce gut homing is restricted to LSECs. Conclusion: The capacity to promote gut tropism via vitamin A use is not unique for intestinal DCs but is also a feature of LSECs. Our data support the assumption that CD4+ T cells can migrate from the liver to the gut as one branch of a postulated enterohepatic lymphocyte circulation.
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Vitamin A from HSCs is converted by neighboring LSECs to RA, which primes CD4+ T cells to acquire a gut-homing phenotype mediated by α4β7 integrin and CCR9 expression.
“Vitamin A from HSCs is converted by neighboring LSECs to RA which primes CD4+ T cells to acquire a gut-homing phenotype mediated by α4β7 integrin and CCR9 expression (42, 138).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [138]
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- Authors
- Neumann, K., Kruse, N., Szilagyi, B., Erben, U., Rudolph, C., Flach, A., Zeitz, M., Hamann, A., & Klugewitz, K.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Klugewitz, Katja
- Venue
- Hepatology
- Published
- 2012-06
- Volume
- 55
- Issue
- 6
- Pages
- 1976-1984
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W1984894605
- Cited by
- 39
- References
- 35
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2022: 3 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 9 · 2014: 6 · 2013: 3 · 2012: 1
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB633, KL 1183/2-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- liver sinusoidal endothelial cells, CD4+ T cells, retinoic acid, vitamin A, alpha4beta7 integrin, CCR9, intestinal dendritic cells, T cell migration, retinal dehydrogenase, inflammatory bowel disease
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Aldehyde Oxidoreductases, Amino Acid Sequence, Animals, Cell Movement, Enterohepatic Circulation, Intestines, Isoenzymes, Liver, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Tretinoin, CD4-Positive T-Lymphocytes, Integrins, Tropism, Endothelial Cells, Retinal Dehydrogenase, Mice, Receptors, CCR
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