Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity

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 pr...

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Published in:JCI insight 2020-05, Vol.5 (9)
Main Authors: Walton, Kelly, Fernandez, Mario R, Sagatys, Elizabeth M, Reff, Jordan, Kim, Jongphil, Lee, Marie Catherine, Kiluk, John V, Hui, Jane Yuet Ching, McKenna, Jr, David, Hupp, Meghan, Forster, Colleen, Linden, Michael A, Lawrence, Nicholas J, Lawrence, Harshani R, Pidala, Joseph, Pavletic, Steven Z, Blazar, Bruce R, Sebti, Said M, Cleveland, John L, Anasetti, Claudio, Betts, Brian C
Format: Article
Language:English
Subjects:
Animals
Graft Rejection - immunology
Graft Rejection - metabolism
Graft vs Host Disease - immunology
Graft vs Host Disease - metabolism
Humans
Mice
Oxidation-Reduction
STAT3 Transcription Factor - physiology
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.136437