Bone marrow or stem cell transplantation
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a viable treatment option for high-risk leukemia and immunodeficiency, but its use is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Novel therapies to prevent GVHD, while protecting beneficial immune responses, are critical for the future success of alloHSCT. It is increasingly recognized that metabolic reprogramming plays a prominent role in T cells during activation. Here, we examined the role of AMP-activated protein kinase (AMPK), a cellular energy sensor, in alloreactive T cells during the development of GVHD. AMPK activity increased > 15-fold early post-transplant, while transplantation of T cells doubly deficient in AMPKα1/α2 decreased GVHD severity in three separate models. Importantly, disease severity decreased without compromising anti-leukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased effector T cell numbers while increasing regulatory T cell (Treg) percentages, all without impacting fat oxidation, autophagy, or mammalian target of rapamycin signaling. Differences in GVHD severity were directly attributable to perturbations in conventional T cells, as depletion of donor Treg minimally impacted the improvements seen using AMPK knock-out cells. Together, these results dissociate AMPK from three classically-ascribed pathways, demonstrate that Treg development can occur in the absence of AMPK, and indicate a prominent role for AMPK in alloreactive T cells. These studies also suggest that AMPK inhibition may offer a novel way to prevent clinical GVHD while still preserving graft-versus-leukemia responses and allowing for robust immune reconstitution.