Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease
Standard
Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease. / Raha, Solaiman; Raud, Brenda; Oberdörfer, Linda; Castro, Carla N; Schreder, Alina; Freitag, Jenny; Longerich, Thomas; Lochner, Matthias; Sparwasser, Tim; Berod, Luciana; Koenecke, Christian; Prinz, Immo.
in: EUR J IMMUNOL, Jahrgang 46, Nr. 9, 09.2016, S. 2233-8.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
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 -