title: Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease.
abstract: 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.
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Solaiman
authors.initials: S
authors.lastname: Raha
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Brenda
authors.initials: B
authors.lastname: Raud
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Oberdörfer
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Carla N
authors.initials: CN
authors.lastname: Castro
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Schreder
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Freitag
authors.affiliation: Institute of Pathology, Universitätsklinikum Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lochner
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Berod
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.|Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Koenecke
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany. prinz.immo@mh-hannover.de.
authors.forename: Immo
authors.initials: I
authors.lastname: Prinz
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000172:deficiency; D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000096:biosynthesis*; D017353:Gene Deletion; D006086:Graft vs Host Disease / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control*; D016130:Immunophenotyping; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D010641:Phenotype; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D005227:Fatty Acids; D018942:Macrolides; C086151:soraphen A; C000616953:ACC1 protein, mouse; D000103:Acetyl-CoA Carboxylase
keywords: Acetyl-CoA carboxylase 1; Foxp3+ regulatory T cells; Graft-versus-host disease; Metabolism; T cells