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  1. Article ; Online: Metabolic Pathways in Alloreactive T Cells

    Rebecca A. Brown / Craig A. Byersdorfer

    Frontiers in Immunology, Vol

    2020  Volume 11

    Abstract: Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative therapy for a range of hematologic illnesses including aplastic anemia, sickle cell disease, immunodeficiency, and high-risk leukemia, but the efficacy of aHSCT is often undermined ... ...

    Abstract Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative therapy for a range of hematologic illnesses including aplastic anemia, sickle cell disease, immunodeficiency, and high-risk leukemia, but the efficacy of aHSCT is often undermined by graft-versus-host disease (GVHD), where T cells from the donor attack and destroy recipient tissues. Given the strong interconnection between T cell metabolism and cellular function, determining the metabolic pathways utilized by alloreactive T cells is fundamental to deepening our understanding of GVHD biology, including its initiation, propagation, and potential mitigation. This review summarizes the metabolic pathways available to alloreactive T cells and highlights key metabolic proteins and pathways linking T cell metabolism to effector function. Our current knowledge of alloreactive T cell metabolism is then explored, showing support for glycolysis, fat oxidation, and glutamine metabolism but also offering a potential explanation for how these presumably contradictory metabolic findings might be reconciled. Examples of additional ways in which metabolism impacts aHSCT are addressed, including the influence of butyrate metabolism on GVHD resolution. Finally, the caveats and challenges of assigning causality using our current metabolic toolbox is discussed, as well as likely future directions in immunometabolism, both to highlight the strengths of the current evidence as well as recognize some of its limitations.
    Keywords alloreactive T cells ; GVHD biology ; immunometabolism ; glycolysis ; fatty acid oxidation (FAO) ; mammalian target of rapamycin (mTOR) ; Immunologic diseases. Allergy ; RC581-607
    Subject code 570
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells

    Darlene A. Monlish / Kevin J. Beezhold / Pailin Chiaranunt / Katelyn Paz / Nathan J. Moore / Andrea K. Dobbs / Rebecca A. Brown / John A. Ozolek / Bruce R. Blazar / Craig A. Byersdorfer

    JCI Insight, Vol 6, Iss

    2021  Volume 14

    Abstract: Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and ... ...

    Abstract Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4+ and CD8+ effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.
    Keywords Metabolism ; Transplantation ; Medicine ; R
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  3. Article: Rethinking the paradigm: How comparative studies on fatty acid oxidation inform our understanding of T cell metabolism

    Chiaranunt, Pailin / Craig A. Byersdorfer / James L.M. Ferrara

    Molecular Immunology. 2015 Dec., v. 68

    2015  

    Abstract: The classic paradigm of T cell metabolism posits that activated Teff cells utilize glycolysis to keep pace with increased energetic demands, while resting and Tmem cells rely on the oxidation of fat. In contrast, Teff cells during graft-versus-host ... ...

    Abstract The classic paradigm of T cell metabolism posits that activated Teff cells utilize glycolysis to keep pace with increased energetic demands, while resting and Tmem cells rely on the oxidation of fat. In contrast, Teff cells during graft-versus-host disease (GVHD) increase their reliance on oxidative metabolism and, in particular, on fatty acid oxidation (FAO). To explore the potential mechanisms driving adoption of this alternative metabolism, we first review key pathways regulating FAO across a variety of disparate tissue types, including liver, heart, and skeletal muscle. Based upon these comparative studies, we then outline a consensus network of transcriptional and signaling pathways that predict a model for regulating FAO in Teff cells during GVHD. This model raises important implications about the dynamic nature of metabolic reprogramming in T cells and suggests exciting future directions for further study of in vivo T cell metabolism.
    Keywords aerobiosis ; beta oxidation ; glycolysis ; heart ; in vivo studies ; liver ; models ; signal transduction ; skeletal muscle ; T-lymphocytes ; transcription (genetics)
    Language English
    Dates of publication 2015-12
    Size p. 564-574.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 424427-8
    ISSN 1872-9142 ; 0161-5890
    ISSN (online) 1872-9142
    ISSN 0161-5890
    DOI 10.1016/j.molimm.2015.07.023
    Database NAL-Catalogue (AGRICOLA)

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