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Natural killer (NK) cells play a dichotomous role in alloimmune responses because they are known to promote both allograft survival and rejection. The aim of this study was to investigate the role of functionally distinct NK cell subsets in alloimmunity with the hypothesis that this dichotomy is explained by the functional heterogeneity of distinct NK cell subsets.Because T-bet controls thematuration of NK cells from CD27high to terminally differentiated CD27low NK cells, we used Rag−/−T-bet−/− mice that lackmature CD27low NK cells to study the distinct roles of CD27low versus CD27high NK cells in a model of Tcell–mediated skin transplant rejection under costimulatory blockade conditions.We found that T cell–reconstituted Rag1−/− recipients (possessing CD27low NK cells) show significantly prolonged allograft survival on costimulatory blockade when compared to Rag1−/−T-bet−/− mice (lacking CD27low NK cells), indicating that CD27low but not CD27high NK cells enhance allograft survival. Critically, Rag1−/−T-bet−/− recipients showed strikingly increased alloreactive memory CD8+ Tcell responses, as indicated by increased CD8+ Tcell proliferation and interferon-γ production. Therefore, we speculated that CD27low NK cells directly regulate alloreactive CD8+ Tcell responses under costimulatory blockade conditions. To test this, we adoptively transferred CD27low NK cells into Rag1−/−T-bet−/− skin transplant recipients and found that the CD27low NK cells restore better allograft survival by inhibiting the proliferation of alloreactive interferon-γ+CD8+ T cells.In summary, mature CD27low NK cells promote allograft survival under costimulatory blockade conditions by regulating alloreactive memory CD8+ T-cell responses.

The following position paper summarizes the recommendations for early clinical trials and ongoing basic research in the field of mesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meeting of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late 2008.

It has recently been recognized that mesenchymal stem cells (MSCs) isolated from adult bone marrow are able to modify the alloimmune response in vitro and in vivo. MSCs can be expanded into large quantities in culture, thereby facilitating potential future applications in solid organ transplantation. To develop novel MSC-based antirejection treatments, the mechanism behind the immunomodulatory ability of MSCs has to be elucidated further. At present, a variety of possible in vitro effects of MSCs on immune system effector cells have been reported, but little is known about their in vivo properties. Here, we discuss recent findings regarding the influence of MSCs on different effector cell populations in vitro and summarize the available data describing their in vivo properties.