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

• DOI: 10.1172/jci.insight.143811
• Publication Date: 2021-07-21T18:01:16Z
• 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
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Transplantation; R; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; AMP-Activated Protein Kinases; Severity of Illness Index; T-Lymphocytes, Regulatory; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Metabolism; Medicine; Animals; Humans; Transplantation, Homologous; Female; Research Article; Bone Marrow Transplantation

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.