The role of interleukin-12 and interferon-gamma in GVHD and GVL

The production of interleukin (IL)-12 by antigen-presenting cells after antigen stimulation is a critical step for initiating antigen-specific cellular immune responses, and interferon (IFN)-gamma produced by natural killer cells and activated T cells is a potent mediator of IL-12 effect. However, recent studies have demonstrated that administration of exogenous IL-12 paradoxically inhibits antigen-specific immunity of T cells in vivo, including allogeneic, autoimmune, and viral antigen-initiated T-cell responses. Interestingly, these inhibitory effects are also mediated by IFN-gamma, whose production is induced by IL-12. Thus, IL-12, a potent immunostimulatory cytokine, can paradoxically lead to immunosuppression. Notably, this cytokine has been shown to preserve graft-versus-leukemia (GVL) effects of allogeneic CD8+ T cells while inhibiting graft-versus-host disease (GVHD) in murine allogeneic bone marrow transplantation models. This article will review recent studies concerning the effect of IL-12 and IFN-gamma on the development of GVHD and the induction of GVL effects, and discuss the possible mechanisms responsible for IL-12-mediated separation of GVL effects from the GVHD-promoting activity of allogeneic T cells.