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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere143811
JournalJCI Insight
Volume6
Issue number14
DOIs
StatePublished - Jul 22 2021

Bibliographical note

Funding Information:
This work was supported by grants to CAB from the NIH/National Heart, Lung, and Blood Institute (NIH/NHLBI) (K08 HL123631, R01 HL144556); Children’s Hospital of Pittsburgh Research Advisory Committee; the University of Pittsburgh Physicians Academic Foundation; the Hyundai Motor Company (Hope on Wheels Scholar grant); the American Society of Hematology (Scholar award); and the Be the Match Foundation (Amy Strelzer Manasevit award); grants to BRB from the NIH/NHLBI (R01 HL11879), NIH/National Cancer Institute (NIH/NCI) (P01 CA142106), and NIH/National Institute of Allergy and Infectious Diseases (P01 AI056299); and grants to KP from the NIH/NCI (T32 CA009138).

Publisher Copyright:
Copyright: © 2021, Monlish et al.

PubMed: MeSH publication types

  • Journal Article

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