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 Anasetti; Brian C. Betts

doi:10.1172/jci.insight.136437

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 journal › Article › peer-review

11 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 language	English (US)
Article number	e136437
Journal	JCI Insight
Volume	5
Issue number	9
DOIs	https://doi.org/10.1172/jci.insight.136437
State	Published - 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1172/jci.insight.136437

OpenUrl availability

Full text

Cite this

Walton, K., Fernandez, M. R., Sagatys, E. M., Reff, J., Kim, J., Lee, M. C., Kiluk, J. V., Hui, J. Y. C., McKenna, D., Hupp, M., Forster, C., Linden, M. A., Lawrence, N. J., Lawrence, H. R., Pidala, J., Pavletic, S. Z., Blazar, B. R., Sebti, S. M., Cleveland, J. L., ... Betts, B. C. (2020). Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity. JCI Insight, 5(9), Article e136437. https://doi.org/10.1172/jci.insight.136437

Walton, K, Fernandez, MR, Sagatys, EM, Reff, J, Kim, J, Lee, MC, Kiluk, JV, Hui, JYC , McKenna, D, Hupp, M, Forster, C, Linden, MA, Lawrence, NJ, Lawrence, HR, Pidala, J, Pavletic, SZ, Blazar, BR, Sebti, SM, Cleveland, JL, Anasetti, C & Betts, BC 2020, 'Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity', JCI Insight, vol. 5, no. 9, e136437. https://doi.org/10.1172/jci.insight.136437

@article{bb3c9dcaa7744b3088846ee83ff0d4b2,

title = "Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity",

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.",

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

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: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = may,

day = "7",

doi = "10.1172/jci.insight.136437",

language = "English (US)",

volume = "5",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "9",

}

TY - JOUR

T1 - Metabolic reprogramming augments potency of human pSTAT3-inhibited iTregs to suppress alloreactivity

AU - Walton, Kelly

AU - Fernandez, Mario R.

AU - Sagatys, Elizabeth M.

AU - Reff, Jordan

AU - Kim, Jongphil

AU - Lee, Marie Catherine

AU - Kiluk, John V.

AU - Hui, Jane Yuet Ching

AU - McKenna, David

AU - Hupp, Meghan

AU - Forster, Colleen

AU - Linden, Michael A.

AU - Lawrence, Nicholas J.

AU - Lawrence, Harshani R.

AU - Pidala, Joseph

AU - Pavletic, Steven Z.

AU - Blazar, Bruce R.

AU - Sebti, Said M.

AU - Cleveland, John L.

AU - Anasetti, Claudio

AU - Betts, Brian C.

N1 - 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.

PY - 2020/5/7

Y1 - 2020/5/7

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85084379456&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85084379456&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.136437

DO - 10.1172/jci.insight.136437

M3 - Article

C2 - 32255769

AN - SCOPUS:85084379456

SN - 2379-3708

VL - 5

JO - JCI Insight

JF - JCI Insight

IS - 9

M1 - e136437

ER -

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

Abstract

Bibliographical note

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this