Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid.
The liver has long been described as immunosuppressive, although the mechanisms underlying this phenomenon are incompletely understood. Hepatic stellate cells (HSCs), a population of liver nonparenchymal cells, are potent producers of the regulatory T cell (Treg)-polarizing molecules TGF-β1 and all-trans retinoic acid, particularly during states of inflammation. HSCs are activated during hepatitis C virus infection and may therefore play a role in the enrichment of Tregs during infection. We hypothesized that Ag presentation in the context of HSC activation will induce naive T cells to differentiate into Foxp3(+) Tregs. To test this hypothesis, we investigated the molecular interactions between murine HSCs, dendritic cells, and naive CD4(+) T cells. We found that HSCs alone do not present Ag to naive CD4(+) T cells, but in the presence of dendritic cells and TGF-β1, preferentially induce functional Tregs. This Treg induction was associated with retinoid metabolism by HSCs and was dependent on all-trans retinoic acid. Thus, we conclude that HSCs preferentially generate Foxp3(+) Tregs and, therefore, may play a role in the tolerogenic nature of the liver.
Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Richard M
RM
Dunham
Manoj
M
Thapa
Victoria M
VM
Velazquez
Elizabeth J
EJ
Elrod
Timothy L
TL
Denning
Bali
B
Pulendran
Arash
A
Grakoui
D000818:Animals; D017951:Antigen Presentation; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance; D008099:Liver / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D014212:Tretinoin / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053773:Transforming Growth Factor beta1; D014212:Tretinoin