The liver has been generally considered an organ prone to tolerance induction and maintenance. However, whether and how the unique liver microenvironment contributes to tolerance maintenance is largely unknown. Here, we used liver fibroblastic stromal cells to mimic the liver microenvironment and found that liver stroma could induce Lin ؊ CD117 ؉ progenitors to differentiate into dendritic cells (DCs) with low CD11c, MHC II but high CD11b expression, high IL-10, but low IL-12 secretion. Such regulatory DCs could inhibit T-cell proliferation in vitro and in vivo, induce apoptosis of the activated T cells, and alleviate the damage of autoimmune hepatitis. Furthermore, liver stroma-derived macrophage colonystimulating factor (M-CSF) was found to contribute to the generation of such regulatory DCs. Regulatory DC-derived PGE2 and T cell-derived IFN-gamma were responsible for the regulatory function. The natural counterpart of regulatory DCs was phenotypically and functionally identified in the liver. Importantly, Lin ؊ CD117 ؉ progenitors could be differentiated into regulatory DCs in the liver once transferred into the liver. Infusion with liver regulatory DCs alleviated experimental autoimmune hepatitis. Therefore, we demonstrate that the liver microenvironment is highly important to program progenitors to differentiate into regulatory DCs in situ, which contributes to the maintenance of liver tolerance. (Blood. 2008; 112:3175-3185)
IntroductionThe liver is a unique organ in which induction of tolerance may be favored over induction of immunity. There is a great deal of experimental and clinical evidence that support such an observation. For example, administration of antigens via the portal vein was found to induce immune tolerance, 1 and allogeneic liver transplantation could be established and maintained even without immunosuppression. 2 In addition, pathogens, such as hepatitis B virus, can cause chronic infection in the liver even after the initiation of immune response. 3,4 The phenomenon of "liver tolerance" has drawn much attention; however, the underlying mechanisms are not fully understood.Up to now, most studies on the mechanisms of liver tolerance mainly focused on the behavior of lymphocytes and antigenpresenting cells (APCs) in the liver. Natural killer (NK) and NKT cells rich in the liver can secrete chemokines to trap the activated T cells to undergo cell death in liver, 5-7 which was proposed as one reason for liver tolerance. Another explanation was that some DCs in the liver secrete IL-10, which in turn induces tolerance. [7][8][9] However, considering that such cells exist all over the body, we wonder why and how they can preferentially induce tolerance in the liver.As a heterogeneous population of APCs, DCs play pivotal roles in the initiation of immunity and induction of immunologic tolerance depending on their maturation state and subsets. [10][11][12] Recently, DCs with regulatory functions have attracted much attention because they can inhibit T-cell response and inflammation. On the basis ...
