Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Significance Mesenchymal stem/stromal cells (MSCs) are the focus of intensive efforts directed at developing cell-based therapies in immunologic disorders. However, one of the paradoxical observations made so far is that MSCs engraft transiently in the recipient after exogenous infusion, but achieve long-term therapeutic benefits. Here we demonstrate that MSCs induce the immune tolerance by activating endogenous immune regulatory system of the recipient. Specifically, i.v. administered MSCs induce a population of regulatory monocytes/macrophages in the lung, which are capable of suppressing allo- and autoimmune responses independently of regulatory T cells. The data provide a mechanistic insight into the action of MSCs in immunologic disorders, one of the most frequent indications of diseases for clinical trials using stem cells. Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α–stimulated gene/protein (TSG)-6–dependent manner. As a result, mice were protected against subsequent immune challenge in two models of allo- and autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell–suppressive activities independently of FoxP3+ regulatory T cells. Adoptive transfer of MSC-induced B220+CD11b+ monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II+B220+CD11b+ cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages.