Liver transplant tolerance was initially discovered in pigs, rats and mice. A recent paper reviewed ∼400 liver transplant patients worldwide who had undergone weaning of immunosuppression, and demonstrated that ∼1/4 achieved complete independence of immunosuppression. To understand the underlying mechanisms, we established a liver transplant model in mice, and found that liver transplant tolerance requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine, as IFN-γ receptor knockout liver grafts are acutely rejected in in allogeneic WT recipients. The breakdown in tolerance in IFN-γR1^-/- liver graft is not a result of the loss of IFN-γ signaling in graft CD45⁺ hematopoietic cells since they are rapidly replaced by WT cells of recipient origin. Tolerance is in fact effected by the graft CD45^– mesenchymal cells; infiltrating allogeneic effector T cells (Tef) activate IFN-γ signaling in graft mesenchymal cells resulting in increased expression of B7-H1 which in turn leads to Tef apoptosis. We have identified hepatic stellate cells (HpSC) as the most potent immune suppressive population in the liver. HpSC markedly suppress the T cell response in MLR cultures. In vivo the co-transplantation of HpSC protects islet allografts from rejection. HpSC isolated from IFN-γR^-/- or B7-H1^-/- mice fail to protect co-transplanted islet allografts. This data indicates that the IFN-γ/B7-H1 signaling pathway in liver mesenchymal cells is a critical regulator of the local immune response in the liver. ATF5 (activating transcription factor 5), a member of the ATF/CREB family, is highly abundant liver-enriched transcription factor, but its role in the liver has not been extensively investigated. In order to elucidate its precise role we generated ATF5 knockout mice. Homozygous ATF5^-/- pups had a 90% perinatal mortality rate. Interestingly, liver mesenchymal cells isolated from ATF5^-/- mice were notable for a marked reduction in IFN-γ/B7-H1 signaling activity, suggesting that ATF5 participates in immune regulation in the liver. A better understanding of the molecular mechanisms of local immune regulation in the liver will enlighten novel strategies for the induction of transplant tolerance and the treatment of autoimmune and viral hepatitis.

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