Interleukin-27 enhances the function of regulatory T cells to prevent Graft-versus-host diseases

Abstract

Abstract Graft-versus-host diseases (GvHD) remain life-threatening complications after allogeneic stem cell transplantation. Foxp3+Tregs can inhibit GvHD, while preserving graft-versus-tumor activity, making Tregs a promising candidate for GvHD treatment. Yet, the clinical application is hampered by the limited numbers and ineffective functions during treatment. Conventional CD4 T cells acquire Foxp3 expression and regulatory functions by stimulating them with IL-2 and TGFb (iTregs). Unlike thymus-derived Tregs (tTreg), ineffective regulatory functions and phenotypic instability of iTregs remain areas of improvement. We reported that IL-27 is able to enhance Treg functions to reduce autoimmune and allergic inflammation. Herein, we sought to test if IL-27-stimulation in Tregs improves therapeutic efficacy of Tregs in a murine model of MHC-mismatched allogeneic GvHD. IL-27-pretreated tTregs efficiently reduced acute GvHD-associated mortality, whereas the efficacy of IL-27-pretreated polyclonal iTregs to prevent GvHD was marginal. We hypothesized that elevating antigen specificity in iTregs would increase the therapeutic functions of iTregs. Indeed, IL-27-pretreated allogeneic iTregs exhibited highly improved therapeutic function, equivalent to that of tTregs. IL-27-induced iTreg functions were also tested using human cells. IL-27 prestimulated third party human iTregs partially rescued mice from xenogeneic GvHD. Our data suggest that IL-27 stimulation in Tregs may play an important role in regulating Treg functions during GvHD, raising the hypothesis that defects in Treg functions (possibly via IL-27) may underlie different susceptibility of allogeneic bone marrow transplant patients who develop GvHD or not.