Successful organ transplantation relies on lifelong immunosuppression, associated with severe side effects. Induction of tolerance is ideal but elusive in clinic. Indeed spontaneous liver transplant tolerance occurs frequently in both animals and humans with unclear mechanism. We were inspired by an unexpected phenomenon that the liver transplant tolerance absolutely requires rejection cytokine interferon (IFN)-γ and investigated the rejection of IFN-γ receptor knockout liver allograft in WT recipients. We revealed that the rejection of IFN-γR1^-/- liver graft is not mediated by graft CD45⁺ hematopoietic immune cells because they rapidly replaced by WT cells of recipient origin. It is rather mediated by the graft CD45^– mesenchymal cells. IFN-γ (derived from T effectors (Tef) cells) ligation on graft mesenchymal cells triggers the upregulation of B7-H1expression leading to the apoptosis of the infiltrating Tefs. This documentes that the allograft equips machinery to counterattack the host immune response through mesenchyma-mediated immune control (MMIC) mechanism. The MMIC represents the intrinsic negative feedback loop cascades between graft mesenchymal cells and effector T cells leading to liver tolerance. Comparable elevations of Treg cells and MDSC are seen in both rejection and tolerance groups, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells (HpSC) and liver sinusoid endothelial cells (LSEC). Addition of either HpSC or LSEC markedly suppresses T cell response in MLR cultures. Co-transplantation with HpSC or LSEC significantly prolongs survival of islet allografts. HpSC isolated from IFN-γR^-/- or B7-H1^-/- mice fail to protect the co-transplanted islet allografts, indicating critical role of IFN-γ/B7-H1 signaling pathway in immune regulation. Inhibitory activity of MMCI is unlikely exclusive to the liver, as spontaneous acceptance of kidney allograft has been reported, although less common, probably reflecting variance in MMIC activity between individual organs. MMIC may represent an important homeostatic mechanism that supports peripheral tolerance. MMIC orchestrated by the allograft may represent a novel target for the induction of transplant tolerance. Graft plays a key role in the equipoise between tolerance and rejection and warrants attention in the search for biomarkers of tolerance.

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