Hepatic Stellate Cells Function as Regulatory Bystanders

Abstract

Regulatory T cells (Treg) 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 (VitA) metabolite, retinoic acid (RA), as a key-controller, which 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 naïve OT-II TCR transgenic (OT-II) CD4+T cells and only moderately stimulated α-GalCer primed invariant NKT (iNKT) cells. In contrast, HSC functioned as regulatory bystanders and promoted enhanced Foxp3 induction by OT-II T cells primed by spleen dendritic cells (DC) whereas they greatly inhibited the Th17 differentiation. Furthermore, the regulatory bystander capacity of the HCS 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.

Immunofluorescence identifies distinct subsets of endothelial cells in the human liver

“…We provided quantified evidence of the existence of Type 1 and Type 2 LSEC, and the differences in intensity of markers expressed in PT and CV(see Supplementary Information), but quantification of cells such as sinusoidal endothelia must be interpretted with caution, our quantification provides further evidence of our observed findings, but it must be emphasized that the findings in this paper are intended to be descriptive. Stellate cells have been described as being aSMA mid32 , CD271 + 33 , and are CD146 + in animals 34 , lining the abluminal surface 32 of the sinus. We used aSMA and CD146 to clearly demarcate stellate cells from adjacent CD105 + LSEC and describe a lobular distribution of these cells.…”

Immunotherapy for hepatocellular carcinoma

“…HSCs act as immune cells by expressing antigen presenting associated molecules, similar to LSECs and KCs, including MHC I, MHC II, CD80 and CD86 (17,18). In another study, HSCs failed to perform as APCs since expression of key molecules required for antigen presentation were not observed (19). HSCs may participate in immune regulation by other manners.…”

Human hepatic stellate cell isolation and characterization

“…HSCs release inflammatory, proliferative, and fibrogenic cytokines such as IL-6, PDGF, and TGFb, through direct contact with their neighboring cells [18]. It is reported that HSCs can also function as regulatory bystander and contribute to liver-induced tolerance [19]. HSCs also contribute to liver regeneration [20], and potentially mediate sinusoidal blood flow via contraction and regulate microvascular structure and function in liver [21].…”