T-cell Metabolism as a Target to Control Autoreactive T Cells in β-Cell Autoimmunity

Bordignon, Carlotta; Canu, Adriana; Dyczko, Aleksandra; Leone, Serena; Monti, Paolo

doi:10.1007/s11892-017-0848-5

Cited by 9 publications

(11 citation statements)

References 57 publications

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“…With respect to potential side effects of GLUT1 inhibition in humans, studies of the GLUT1 deficiency syndrome reported mild to severe neurological disorders in infants and children affected, whereas in adult life, most symptoms were stable or diminished (37). Since overexpression of GLUT1 is not limited to autoreactive T cells and metabolism is increased in activated T cells, we can envisage a strategy in which adult patients undergoing islet transplantation have a selective reactivation of autoreactive T-cell clones (38). This model provides the opportunity for using WZB117 for a limited time period and increasing the selectivity of the treatment for activated autoreactive T cells that upregulate glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes

et al. 2018

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Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8 Tscm specific for β-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes

et al. 2018

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“…Because the metabolism of T lymphocytes is so closely linked to their activation, differentiation, and survival, there is tremendous interest in manipulating metabolic processes for therapeutic purposes. This topic has been well reviewed recently ( 112 – 115 ) so only a brief summary of potential lipid metabolic drug targets will be described here. It is likely that many existing drugs used to normalize metabolic imbalances might be “repositioned” for use in other indications including treatment of autoimmunity and graft-versus-host disease (GVHD).…”

Section: A Role For Lipid Metabolism In T-cell Subset Differentiationmentioning

confidence: 99%

The Role of Lipid Metabolism in T Lymphocyte Differentiation and Survival

et al. 2018

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The differentiation and effector functions of both the innate and adaptive immune system are inextricably linked to cellular metabolism. The features of metabolism which affect both arms of the immune system include metabolic substrate availability, expression of enzymes, transport proteins, and transcription factors which control catabolism of these substrates, and the ability to perform anabolic metabolism. The control of lipid metabolism is central to the appropriate differentiation and functions of T lymphocytes, and ultimately to the maintenance of immune tolerance. This review will focus on the role of fatty acid (FA) metabolism in T cell differentiation, effector function, and survival. FAs are important sources of cellular energy, stored as triglycerides. They are also used as precursors to produce complex lipids such as cholesterol and membrane phospholipids. FA residues also become incorporated into hormones and signaling moieties. FAs signal via nuclear receptors and their channeling, between storage as triacyl glycerides or oxidation as fuel, may play a role in survival or death of the cell. In recent years, progress in the field of immunometabolism has highlighted diverse roles for FA metabolism in CD4 and CD8 T cell differentiation and function. This review will firstly describe the sensing and modulation of the environmental FAs and lipid intracellular signaling and will then explore the key role of lipid metabolism in regulating the balance between potentially damaging pro-inflammatory and anti-inflammatory regulatory responses. Finally the complex role of extracellular FAs in determining cell survival will be discussed.

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“…Importantly, adaptive memory responses are also very well known to play a crucial part in autoimmune diseases. However, the role of the adaptive immune system in these diseases has been discussed elsewhere in very good recent review articles ( 19 – 21 ) and was therefore not included in this review.…”

Section: Introductionmentioning

confidence: 99%

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

2018

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During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.

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T-cell Metabolism as a Target to Control Autoreactive T Cells in β-Cell Autoimmunity

Cited by 9 publications

References 57 publications

Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes

Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes

The Role of Lipid Metabolism in T Lymphocyte Differentiation and Survival

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

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