Abstract
Immunosuppressive donor Tregs can prevent graft-versus-host disease (GVHD) or solid-organ allograft rejection. We previously demonstrated that inhibiting STAT3 phosphorylation (pSTAT3) augments FOXP3 expression, stabilizing induced Tregs (iTregs). Here we report that human pSTAT3-inhibited iTregs prevent human skin graft rejection and xenogeneic GVHD yet spare donor antileukemia immunity. pSTAT3-inhibited iTregs express increased levels of skin-homing cutaneous lymphocyte-associated antigen, immunosuppressive GARP and PD-1, and IL-9 that supports tolerizing mast cells. Further, pSTAT3-inhibited iTregs significantly reduced alloreactive conventional T cells, Th1, and Th17 cells implicated in GVHD and tissue rejection and impaired infiltration by pathogenic Th2 cells. Mechanistically, pSTAT3 inhibition of iTregs provoked a shift in metabolism from oxidative phosphorylation (OxPhos) to glycolysis and reduced electron transport chain activity. Strikingly, cotreatment with coenzyme Q10 restored OxPhos in pSTAT3-inhibited iTregs and augmented their suppressive potency. These findings support the rationale for clinically testing the safety and efficacy of metabolically tuned, human pSTAT3-inhibited iTregs to control alloreactive T cells.
Highlights
Human Tregs can suppress alloreactive T cells responsible for graft-versus-host disease (GVHD) and solid-organ allograft rejection [1,2,3,4,5]
We demonstrate that adoptive transfer of human pSTAT3–inhibited induced Tregs (iTregs) prevents skin graft rejection and xenogeneic GVHD by donor T cells
PSTAT3 inhibition in iTregs augments demethylation of the FOXP3 Treg-specific demethylated region (TSDR) and Foxp3 expression, stabilizing their suppressive phenotypic [21], and here we show this is associated with increased expression of the immune checkpoints GARP and PD-1 that are important for the enhanced potency of the pSTAT3-inhibited iTregs
Summary
Human Tregs can suppress alloreactive T cells responsible for graft-versus-host disease (GVHD) and solid-organ allograft rejection [1,2,3,4,5]. Broadly suppressive calcineurin inhibitors (CNI) remain standard of care for preventing GVHD and allograft rejection, yet protection offered by CNIs is incomplete [6,7,8]. Adoptive transfer of human Tregs has been shown safe, and emerging data have shown efficacy in preventing GVHD after allogeneic hematopoietic cell transplantation (alloHCT) [5, 12]. Contemporary phase I/II clinical trials are underway investigating the benefit of human Tregs in the prevention of GVHD and solid-organ transplant rejection [2, 15, 17, 18]
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