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

Kelly Walton, Mario R. Fernandez, Elizabeth M. Sagatys, Jordan Reff, Jongphil Kim, Marie Catherine Lee, John V. Kiluk, Jane Yuet Ching Hui, David McKenna, Meghan Hupp, Colleen Forster, Michael A. Linden, Nicholas J. Lawrence, Harshani R. Lawrence, Joseph Pidala, Steven Z. Pavletic, Bruce R. Blazar, Said M. Sebti, John L. Cleveland, Claudio AnasettiBrian C. Betts

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere136437
JournalJCI Insight
Volume5
Issue number9
DOIs
StatePublished - May 7 2020

Bibliographical note

Funding Information:
Our study received assistance from the Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center & Research Institute (P30-CA076292) and the Flow Cytometry Resource at the University of Minnesota, each National Cancer Institute–designated Comprehensive Cancer Centers. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1-TR002494). We acknowledge the animal care staff in the Department of Comparative Medicine at the University of South Florida and the University of Minnesota Research Animal Resources for providing technical assistance. This work was supported by the Amy Strelzer Manasevit Research Program (to BCB); NIH grant R01 HL133823 (to BCB), R01 HL11879 (to BRB), R01 HL56067 (to BRB), and R37 AI34495 (to BRB); and LLS Translational Research Grant 6462-15 (to BRB).

Publisher Copyright:
© 2020, American Society for Clinical Investigation.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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