Metabolic reprogramming augments potency of human pSTAT3–inhibited iTregs to suppress alloreactivity
Open Access
- 7 May 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
Abstract
Immune suppressive donor regulatory T cells (Tregs) can prevent graft-versus-host disease (GVHD) or solid organ allograft rejection. We previously demonstrated inhibiting STAT3 phosphorylation (pSTAT3) augments FOXP3 expression, stabilizing induced Tregs (iTregs). Here we report human pSTAT3-inhibited iTregs prevent human skin graft rejection and xenogeneic GVHD yet spare donor anti-leukemia immunity. pSTAT3-inhibited iTregs express increased levels of skin-homing CLA antigen, immune suppressive GARP and PD-1, and IL-9 that supports tolerizing mast cells. Further, pSTAT3-inhibited iTregs significantly reduce alloreactive conventional T cells, Th1, and Th17 cells implicated in GVHD and tissue rejection, and impair infiltration by pathogenic Th2 cells. Mechanistically, pSTAT3 inhibition of iTregs provokes a shift in metabolism from oxidative phosphorylation (OxPhos) to glycolysis and reduced electron transport chain activity. Strikingly, co-treatment with coenzyme Q10 (coQ10) restores OxPhos in pSTAT3-inhibited iTregs and augments 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.Funding Information
- National Heart, Lung, and Blood Institute (R01 HL133823)
- National Institutes of Health (R01HL11879)
- National Institutes of Health (R01 HL56067)
- National Institutes of Health (R37 AI34495)
- Amy Strelzer Manasevit Research Program (N/A)
- Leukemia and Lymphoma Society (N/A)
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