Autophagy prevents graft failure during murine Graft versus Host Disease.

Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and GVHD. We demonstrate in vitro that both TNF and IL-1β, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In an MHC mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic SCT and may represent a therapeutic target to prevent graft failure during GVHD.