Myeloid-derived suppressor cells (MDSC) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSC from bone marrow have been shown to enhance survival in an acute model of lethal graft-versus-host disease (GvHD). However, donor MDSC infusion only partially ameliorates GvHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes we set out to investigate the fate of MDSC after transfer in the setting of acute GvHD (aGvHD). MDSC transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGvHD, which we now show directly undermines their suppressive capacity. Under conditioning regimen and GvHD inflammatory settings, MDSC rapidly lose suppressor function and their potential to inhibit GvHD lethality, which is associated with their induced conversion towards a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSC deficient in the adaptor ASC (Apoptosis-associated speck-like protein containing a CARD), that assembles inflammasome complexes, conferred improved survival of mice developing GvHD compared to wild-type donor MDSC. These data suggest the use of MDSC as a therapeutic approach for preventing GvHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation empowering MDSCs to maintain their suppressive potential.
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