Immune regulatory cell therapy to prevent and treat GVHD. A schematic overview of mechanisms by which infused regulatory populations promote tissue regeneration and inhibit T-cell priming and differentiation to attenuate GVHD. Infused regulatory cells may prevent and/or treat GVHD by acting in 3 distinct phases. First, they may promote tissue regeneration following damage by conditioning (when used prophylactically) or from GVHD (when used as treatment). Intermediate secreted molecules from both adaptive and innate cells are highlighted and include amphiregulin, cytokines important in GI tract homeostasis such as IL-22 and IL-17, angiogenic factors such as connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF) as well as regulators of inflammatory responses such as arginase, IDO, heme oxygenase-1 (HO-1), and the reduced NAD phosphate oxygenase isoform (NOX2). Second, regulatory cells may inhibit the APC–T-cell interaction via the release of immunosuppressive cytokines (such as IL-10, TGF-β) or by directly lysing APCs themselves (eg, NK cells). Finally, regulatory populations may suppress donor T-cell differentiation and expansion via a number of secreted immunosuppressive molecules (eg, IL-10, TGF-β, IDO, NO, and ROS) or by directly lysing T cells (NK cells). DAMPS, damage-associated molecular patterns; PAMPS, pathogen-associated molecular patterns; SDF, stromal derived factor-1.