Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: Role of endotoxin and implications for allograft tolerance

Anil Dangi, Tina L. Sumpter, Shoko Kimura, Donna B. Stolz, Noriko Murase, Giorgio Raimondi, Yoram Vodovotz, Chao Huang, Angus W. Thomson, Chandrashekhar R. Gandhi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


Hepatic stellate cells (HSCs) may play an important role in hepatic immune regulation by producing numerous cytokines/chemokines and expressing Ag-presenting and T cell coregulatory molecules. Due to disruption of the endothelial barrier during cold-ischemic storage and reperfusion of liver grafts, HSCs can interact directly with cells of the immune system. Endotoxin (LPS), levels of which increase in liver diseases and transplantation, stimulates the synthesis of many mediators by HSCs. We hypothesized that LPS-stimulated HSCs might promote hepatic tolerogenicity by influencing naturally occurring immunosuppressive CD4 + CD25 +Foxp3 + regulatory T cells (Tregs). Following their portal venous infusion, allogeneic CD4 + T cells, including Tregs, were found closely associated with HSCs, and this association increased in LPS-treated livers. In vitro, both unstimulated and LPSstimulated HSCs upregulated Fas (CD95) expression on conventional CD4 + T cells and induced their apoptosis in a Fas/Fas liganddependent manner. By contrast, HSCs induced Treg proliferation, which required cell-cell contact and was MHC class IIdependent. This effect was augmented when HSCs were pretreated with LPS. LPS increased the expression of MHC class II, CD80, and CD86 and stimulated the production of IL-1α, IL-1β, IL-6, IL-10 and TNF-α by HSCs. Interestingly, production of IL1α, IL-1β, IL-6, and TNF-α was strongly inhibited, but that of IL-10 enhanced in LPS-pretreated HSC/Treg cocultures. Adoptively transferred allogeneic HSCs migrated to the secondary lymphoid tissues and induced Treg expansion in lymph nodes. These data implicate endotoxin-stimulated HSCs as important immune regulators in liver transplantation by inducing selective expansion of tolerance-promoting Tregs and reducing inflammation and alloimmunity.

Original languageEnglish
Pages (from-to)3667-3677
Number of pages11
JournalJournal of Immunology
Issue number8
StatePublished - 15 Apr 2012
Externally publishedYes


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