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; Schreder, Alina; Freitag, Jenny; Longerich, Thomas; Lochner, Matthias; Sparwasser, Tim; Berod, Luciana; Koenecke, Christian; Prinz, Immo

doi:10.1002/eji.201546152

Cited by 42 publications

(33 citation statements)

References 22 publications

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“…In activated T cells, the endogenous synthesis of LCFAs and cholesterol relies heavily on acetyl-CoA obtained in the mitochondria after glycolysis which is exported to the cytoplasm and used to initiate lipid synthesis through a brief conjugation to mitochondrial oxaloacetate to form citrate (Figure 1). Endogenous FAS is necessary to sustain the expansion of activated T cells, as demonstrated by the impaired proliferation and effector response observed after genetic deletion of the SREBP cleavage-activating protein (SCAP) (61) or ACC1 (62, 63, 65, 68). This connection between the glycolytic and lipogenic pathways provides another reason why activated T cells and other cells that vigorously proliferate, such as tumour cells, depend to such degree on an upregulation of the glycolytic pathway, not only to produce ATP, but also to sustain anabolic reactions.…”

Section: Metabolic Changes Defining Cd8+ T Cell Immunitymentioning

confidence: 99%

Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts

Raud

McGuire

Jones

et al. 2018

Immunological Reviews

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112

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Fatty acid metabolism in CD8+ T cell memory CD8+ T cells are key members of the adaptive immune response against infections and cancer. As we discuss in this review, these cells can present diverse metabolic requirements, which have been intensely studied during the past few years. Our current understanding suggests that aerobic glycolysis is a hallmark of activated CD8+ T cells, while naïve and memory (Tmem) cells often rely on oxidative phosphorylation, and thus mitochondrial metabolism is a crucial determinant of CD8+ Tmem cell development. Moreover, it has been proposed that CD8+ Tmem cells have a specific requirement for the oxidation of long-chain fatty acids (LC-FAO), a process modulated in lymphocytes by the enzyme CPT1A. However, this notion relies heavily on the metabolic analysis of in vitro cultures and on chemical inhibition of CPT1A. Therefore, we introduce more recent studies using genetic models to demonstrate that CPT1A-mediated LC-FAO is dispensable for the development of CD8+ T cell memory and protective immunity, and question the use of chemical inhibitors to target this enzyme. We discuss insights obtained from those and other studies analysing the metabolic characteristics of CD8+ Tmem cells, and emphasise how T cells exhibit flexibility in their choice of metabolic fuel.

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Section: Metabolic Changes Defining Cd8+ T Cell Immunitymentioning

confidence: 99%

Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts

Raud

McGuire

Jones

et al. 2018

Immunological Reviews

Self Cite

112

View full text Add to dashboard Cite

show abstract

“…Moreover, Myc is essential for activation of glucose-metabolizing genes and also for FA synthesis, linking glycolysis to de novo FAS ( 45 ). Recent studies showed that FAS is required for maintaining glycolytic activity in allogeneic T cells ( 46 ). Disruption of FAS at ACC1 effectively ameliorates GVHD development ( 46 , 47 ).…”

Section: Metabolism Of Allogeneic T Cellsmentioning

confidence: 99%

“…Recent studies showed that FAS is required for maintaining glycolytic activity in allogeneic T cells ( 46 ). Disruption of FAS at ACC1 effectively ameliorates GVHD development ( 46 , 47 ). This study emphasizes the relationship between glycolysis and FAS in allogeneic T cells.…”

Section: Metabolism Of Allogeneic T Cellsmentioning

confidence: 99%

T-Cell Metabolism in Hematopoietic Cell Transplantation

et al. 2018

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Metabolism, including catabolism and anabolism, is a basic cellular process necessary for cell survival. T lymphocytes have a distinct metabolism that can determine both fate and function. T-cell activation depends on glycolysis to obtain materials and energy for proliferation and effector function. Importantly, T cells utilize different metabolic processes under different conditions and diseases. Allogeneic hematopoietic cell transplantation (allo-HCT) is a classic immunotherapy for hematological malignancies; however, the development of graft-versus-host disease (GVHD) is a major factor limiting the success of allo-HCT. T cells in the donor graft drive GVHD by mounting a robust immunological attack against recipient normal tissues. Hence, understanding T-cell metabolism after allo-HCT would provide potential metabolic targets for the control of GVHD and primary tumor relapse. The purpose of the current review is to highlight the key metabolic pathways involved in alloantigen-activated T cells and to discuss how manipulating these pathways can serve as potential new therapeutic strategies to induce immune tolerance after allo-transplantation. We will also summarize the recent progress in regulating T-cell metabolism in bone marrow transplantation by targeting novel metabolic regulators or immune checkpoint molecules.

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“…Specifically, allo-reactive donor T cells demonstrate increased aerobic glycolysi (11, 12), oxidative phosphorylation (OXPHOS)(13), and fatty acid metabolism (14, 15) resulting in increased oxidative stress. Reactive oxygen species (ROS) production, and thus the degree of oxidative stress, is controlled in part by Sirtuins (SIRTs), which are class III histone deacetylases (HDACs) (16) known to influence a variety of aging related disorders, in part, by controlling mitochondrial functions, including inhibition of ROS production (17, 18).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation

Toubai

Tamaki

Peltier

et al. 2018

The Journal of Immunology

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Allogeneic stem cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT is linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both GVT and GVHD require allogeneic T cell responses, which is an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), a mitochondrial histone deacetylases (HDAC), plays an important role in cellular processes through inhibition of reactive oxygen species (ROS). Non-mitochondrial class of HDACs regulate T cell responses; but the role of mitochondrial HDACs, specifically SIRT3, on donor T cell responses after allo-HCT remain unknown. Herein we report that SIRT3 deficient (SIRT3-/-) donor T cells cause reduced GVHD severity in multiple clinically relevant murine models. The GVHD protective effect of allogeneic SIRT3-/- T cells was associated with a reduction in their activation, reduced CXCR3 expression, and no significant impact on cytokine secretion or cytotoxic functions. Intriguingly, the GVHD protective effect of SIRT3-/- T cells was associated with a reduction in ROS production which is contrary to the effect of SIRT3 deficiency on ROS production in other cells/tissues and likely a consequence of their deficient activation. Notably the reduction in GVHD in the gastrointestinal (GI) tract was not associated with a substantial reduction in the graft-versus-tumor (GVT) effect. Collectively these data reveal that SIRT3 activity promotes allogeneic donor T cell responses and ROS production without altering T cell cytokine or cytolytic functions and identify SIRT3 as a novel target on donor T cells to improve outcomes after allo-HCT.

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

Cited by 42 publications

References 22 publications

Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts

Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts

T-Cell Metabolism in Hematopoietic Cell Transplantation

Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation

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

Cited by 42 publications

References 22 publications

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

T-Cell Metabolism in Hematopoietic Cell Transplantation

Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation

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Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts

Fatty acid metabolism in CD8⁺ T cell memory: Challenging current concepts