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.

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It is well known that some strains of lactic acid bacteria (LAB) can induce IL-12 which plays an important role in modulating immune responses. However, the mechanisms by which LAB induce IL-12 production remain unclear. Here, we examine the role of toll-like receptors (TLR's) and reactive oxygen species (ROS) in IL-12 production by LAB stimulated peritoneal macrophages. Our results indicate that a TLR is not necessary for IL-12 induction by LAB, whilst the universal adaptor protein, MyD88, is essential. Specific strains of LAB induced ROS that correlated with both the frequency of phagocytosis and IL-12 production. Reduction in IL-12 production by NADPH oxidase inhibitors or ROS scavengers demonstrates the crucial role of ROS in IL-12 induction. Interestingly, deficiency of TLR2, 4, 9 or MyD88 did not affect the phagocytosis of LAB strain KW3110, a potent IL-12 inducer, and ROS production was significantly reduced only in MyD88 deficient macrophages. These results suggest the existence of TLR-MyD88 independent LAB recognition and MyD88 related ROS induction mechanisms. We show here the importance of ROS for IL-12 induction and provide new insights into IL-12 induction by LAB.

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