Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease

TY - JOUR

T1 - Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease

AU - Raha, Solaiman

AU - Raud, Brenda

AU - Oberdörfer, Linda

AU - Castro, Carla N

AU - Schreder, Alina

AU - Freitag, Jenny

AU - Longerich, Thomas

AU - Lochner, Matthias

AU - Sparwasser, Tim

AU - Berod, Luciana

AU - Koenecke, Christian

AU - Prinz, Immo

N1 - © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2016/9

Y1 - 2016/9

N2 - Upon antigen-specific or allogeneic activation, T cells sharply increase their metabolic activity to cope with augmented needs for proliferation and effector functions. Therefore, enzymes involved in energy metabolism constitute attractive targets to modulate the activity of pathogenic effector T cells in the setting of graft-versus-host-disease (GVHD). Here, we show that T cells deficient for acetyl-CoA carboxylase 1 (TACC1) are dramatically less pathogenic than wild-type (WT) T cells in a lethal C57BL/6 into BALB/c model of acute GVHD and permitted sustained survival of recipient mice. In line with this clinical observation, higher frequencies of GVHD-suppressing Foxp3(+) regulatory T (Treg) cells were detected in the colon of TACC T-cell recipients. In vitro, T-cell stimulation with allogeneic DCs induced higher proportions of Treg cells but also led to diminished proliferation of TACC1 T cells compared to WT T cells. Furthermore, TACC1 T cells activated by allogeneic DCs showed impaired glycolysis and lipid synthesis. Thus, targeting de novo fatty acid synthesis via acetyl-CoA carboxylase inhibition may be a promising new strategy to prevent GVHD.

AB - Upon antigen-specific or allogeneic activation, T cells sharply increase their metabolic activity to cope with augmented needs for proliferation and effector functions. Therefore, enzymes involved in energy metabolism constitute attractive targets to modulate the activity of pathogenic effector T cells in the setting of graft-versus-host-disease (GVHD). Here, we show that T cells deficient for acetyl-CoA carboxylase 1 (TACC1) are dramatically less pathogenic than wild-type (WT) T cells in a lethal C57BL/6 into BALB/c model of acute GVHD and permitted sustained survival of recipient mice. In line with this clinical observation, higher frequencies of GVHD-suppressing Foxp3(+) regulatory T (Treg) cells were detected in the colon of TACC T-cell recipients. In vitro, T-cell stimulation with allogeneic DCs induced higher proportions of Treg cells but also led to diminished proliferation of TACC1 T cells compared to WT T cells. Furthermore, TACC1 T cells activated by allogeneic DCs showed impaired glycolysis and lipid synthesis. Thus, targeting de novo fatty acid synthesis via acetyl-CoA carboxylase inhibition may be a promising new strategy to prevent GVHD.

KW - Acetyl-CoA Carboxylase/antagonists & inhibitors

KW - Adoptive Transfer

KW - Animals

KW - Biomarkers

KW - Bone Marrow Transplantation

KW - Cell Differentiation

KW - Disease Models, Animal

KW - Fatty Acids/biosynthesis

KW - Gene Deletion

KW - Graft vs Host Disease/etiology

KW - Immunophenotyping

KW - Macrolides/pharmacology

KW - Male

KW - Mice

KW - Phenotype

KW - T-Lymphocytes/cytology

KW - Transplantation, Homologous

U2 - 10.1002/eji.201546152

DO - 10.1002/eji.201546152

M3 - SCORING: Journal article

C2 - 27338930

VL - 46

SP - 2233

EP - 2238

JO - EUR J IMMUNOL

JF - EUR J IMMUNOL

SN - 0014-2980

IS - 9

ER -