1. Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity
- Author
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Brian C. Betts, Kelly Walton, Jane Yuet Ching Hui, Michael A. Linden, Meghan Hupp, Colleen L. Forster, Said M. Sebti, John V. Kiluk, Jongphil Kim, Joseph Pidala, David H. McKenna, Harshani R. Lawrence, Jordan Reff, Bruce R. Blazar, John L. Cleveland, Claudio Anasetti, Mario R. Fernandez, Nicholas J. Lawrence, Steven Z. Pavletic, Marie Catherine Lee, and Elizabeth M. Sagatys
- Subjects
0301 basic medicine ,Graft Rejection ,STAT3 Transcription Factor ,Graft vs Host Disease ,Oxidative phosphorylation ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Antigen ,Immunity ,Animals ,Humans ,STAT3 ,Coenzyme Q10 ,biology ,Chemistry ,General Medicine ,Transplantation ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Phosphorylation ,Signal transduction ,Oxidation-Reduction ,Research Article - 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.
- Published
- 2020