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.
Bibliographical noteFunding 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).
Copyright: © 2021, Monlish et al.
PubMed: MeSH publication types
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