PMID- 32255769 OWN - NLM STAT- MEDLINE DCOM- 20210707 LR - 20211212 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 5 IP - 9 DP - 2020 May 7 TI - Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity. LID - 136437 [pii] LID - 10.1172/jci.insight.136437 [doi] LID - e136437 AB - 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. FAU - Walton, Kelly AU - Walton K AD - Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Fernandez, Mario R AU - Fernandez MR AD - Department of Tumor Biology. FAU - Sagatys, Elizabeth M AU - Sagatys EM AD - Department of Hematopathology and Laboratory Medicine. FAU - Reff, Jordan AU - Reff J AD - Department of Immunology. FAU - Kim, Jongphil AU - Kim J AD - Department of Biostatistics and Bioinformatics, and. FAU - Lee, Marie Catherine AU - Lee MC AD - Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida, USA. FAU - Kiluk, John V AU - Kiluk JV AD - Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida, USA. FAU - Hui, Jane Yuet Ching AU - Hui JYC AD - Department of Surgery. FAU - McKenna, David Jr AU - McKenna D Jr AD - Department of Laboratory Medicine and Pathology, and. FAU - Hupp, Meghan AU - Hupp M AD - Department of Laboratory Medicine and Pathology, and. FAU - Forster, Colleen AU - Forster C AD - Bionet Histology Research Laboratory, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Linden, Michael A AU - Linden MA AD - Department of Laboratory Medicine and Pathology, and. FAU - Lawrence, Nicholas J AU - Lawrence NJ AD - Department of Drug Discovery and. FAU - Lawrence, Harshani R AU - Lawrence HR AD - Department of Drug Discovery and. FAU - Pidala, Joseph AU - Pidala J AD - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA. FAU - Pavletic, Steven Z AU - Pavletic SZ AD - Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. FAU - Blazar, Bruce R AU - Blazar BR AD - Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Sebti, Said M AU - Sebti SM AD - Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia USA. FAU - Cleveland, John L AU - Cleveland JL AD - Department of Tumor Biology. FAU - Anasetti, Claudio AU - Anasetti C AD - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA. FAU - Betts, Brian C AU - Betts BC AD - Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. LA - eng GR - R01 HL133823/HL/NHLBI NIH HHS/United States GR - R01 HL118979/HL/NHLBI NIH HHS/United States GR - R01 HL147324/HL/NHLBI NIH HHS/United States GR - R37 AI034495/AI/NIAID NIH HHS/United States GR - P30 CA076292/CA/NCI NIH HHS/United States GR - R01 HL155114/HL/NHLBI NIH HHS/United States GR - R50 CA211447/CA/NCI NIH HHS/United States GR - R01 HL056067/HL/NHLBI NIH HHS/United States GR - P01 CA142106/CA/NCI NIH HHS/United States GR - P01 AI056299/AI/NIAID NIH HHS/United States GR - P30 CA077598/CA/NCI NIH HHS/United States GR - UL1 TR002494/TR/NCATS NIH HHS/United States GR - P01 CA065493/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200507 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) SB - IM MH - Animals MH - *Graft Rejection/immunology/metabolism MH - *Graft vs Host Disease/immunology/metabolism MH - Humans MH - Mice MH - Oxidation-Reduction MH - STAT3 Transcription Factor/*physiology MH - *T-Lymphocytes, Regulatory/cytology/immunology/metabolism PMC - PMC7253027 OTO - NOTNLM OT - Immunology OT - Signal transduction OT - Stem cell transplantation OT - T cells OT - Transplantation COIS- Conflict of interest: BCB holds a patent (WO2015120436A2) related to CD4(+) T cell pSTAT3 as a marker and therapeutic target of acute GVHD. NJL, HRL, and SMS hold a patent (US7960434B2) related to the composition and use of S3I-201. Neither the inventors nor their institutions have received payment related to claims described in the patents. EDAT- 2020/04/08 06:00 MHDA- 2021/07/08 06:00 PMCR- 2020/05/07 CRDT- 2020/04/08 06:00 PHST- 2020/01/14 00:00 [received] PHST- 2020/04/01 00:00 [accepted] PHST- 2020/04/08 06:00 [pubmed] PHST- 2021/07/08 06:00 [medline] PHST- 2020/04/08 06:00 [entrez] PHST- 2020/05/07 00:00 [pmc-release] AID - 136437 [pii] AID - 10.1172/jci.insight.136437 [doi] PST - epublish SO - JCI Insight. 2020 May 7;5(9):e136437. doi: 10.1172/jci.insight.136437.