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.
Highlights
Allogeneic hematopoietic stem cell transplantation is a lifesaving treatment for hematologic disorders, but its application is limited by acute graft-versus-host disease (GVHD), where donor T cells attack and destroy tissues in the recipient liver, gut, skin, and lung [1]
Allogeneic T cells increase fatty acid oxidation (FAO) by day 7 posttransplant [10], a finding that could be explained by increased AMP kinase (AMPK) activity, subsequent phosphorylation of acetyl CoA-carboxylase (ACC), and liberation of carnitine palmitoyltransferase 1a (CPT1a)
CD45.1+ B6 T cells were transplanted into irradiated CD45.2+ B6xDBA2 F1 (B6D2F1) recipients in a major histocompatibility complex (MHC) mismatch model of GVHD
Summary
Allogeneic hematopoietic stem cell transplantation is a lifesaving treatment for hematologic disorders, but its application is limited by acute graft-versus-host disease (GVHD), where donor T cells attack and destroy tissues in the recipient liver, gut, skin, and lung [1]. GVHD remains a prevalent clinical problem [2], and steroids, as the primary treatment for acute GVHD, encompass a myriad of side effects, including suppression of antiviral and antifungal immunity and increased relapse rates due to suboptimal graft-versus-tumor (GVT) responses [3,4,5]. Increased ETC flux is fundamental to alloreactive T cell survival, as inhibition of either complex I or complex V induces donor cell apoptosis and decreases GVHD severity [11, 12]. These results are consistent with studies in solid organ transplantation, where metabolic inhibition decreases alloreactivity and prolongs graft survival [13]. A clinical role for metabolic inhibition is well established, with targeting of mammalian target of rapamycin (mTOR), which integrates cues for T cell activation, differentiation, and function [14], used for both GVHD prophylaxis and treatment [15]
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