Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL

Two of the major complications that limit the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) are disease relapse and GVHD. Due to their rapid recovery early after allo-HCT and their ability to kill malignant targets without prior exposure, natural killer (NK) cells have been considered one of the main effector cells that mediate early GVL reactions. Conversely, regulatory T ells (Tregs) have proven to be critical in facilitating self-tolerance. Both murine and human studies have demonstrated a significant role for Tregs in the modulation of GVHD after allo-HCT. This article reviews the mechanisms of how these 2 cell types carry out these functions, focusing on the post-allo-HCT period. Surprisingly, relatively few studies have addressed how Tregs and NK cells interact with one another and whether these interactions are antagonistic. Although preclinical studies suggest active cross-talk between NK cells and Tregs, early clinical studies have not shown a detrimental impact of Treg therapy on relapse. Despite this, interruption of tolerogenic signals may enhance the efficacy of NK effector functions. Methods to transiently impair Treg functions and augment NK cell alloreactivity will be discussed.