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 - 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 -
