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Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
Darlene A. Monlish, … , Bruce R. Blazar, Craig A. Byersdorfer
Darlene A. Monlish, … , Bruce R. Blazar, Craig A. Byersdorfer
Published July 22, 2021
Citation Information: JCI Insight. 2021;6(14):e143811. https://doi.org/10.1172/jci.insight.143811.
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Research Article Metabolism Transplantation

Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells

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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.

Authors

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

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Figure 1

Alloreactive T cells selectively activate AMPK by day 7 posttransplant.

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Alloreactive T cells selectively activate AMPK by day 7 posttransplant.
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(A) Two million CD45.1+ T cells and 5 × 106 B6 bone marrow (BM) cells were transplanted into irradiated syngeneic (B6) or allogeneic (B6D2F1) recipients. On day 7 posttransplant, CD45.1+ donor T cells were flow-sorted and cell lysates immunoblotted for total and phosphorylated proteins in the AMPK pathway. Naive, donor T cells prior to transplantation. (B) Ratios of phosphorylated/total AMPK (left), liver kinase B1/Lamin B1 (middle), and phosphorylated/total ACC (right) were calculated based upon densitometry of blots in A. (C) In a separate experiment, day 7 donor cell lysates were blotted for phosphorylated ULK1 (*P-ULK1), with *P-ULK1/LaminB1 ratios calculated as above. In A–C n = 10 animals per condition pooled into 3 separate groups. (D) One million OT-I and 1 × 106 OT-II cells were transplanted into irradiated CAG-OVA mice, followed by flow-sorting of OT-I cells on day 6 after BM transplantation. Immunoblotting compared phospho/total AMPK in pretransplant (naive) versus day +6 OT-I cells (n = 3). Data in each panel represent 3 or more independent experiments. **P < 0.01, ***P < 0.001.

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ISSN 2379-3708

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