β2-adrenergic receptor activation on donor cells ameliorates acute GvHD.

: Acute graft versus host disease (aGvHD) remains a major impediment to successful allogeneic hematopoietic cell transplantation (allo-HCT). To solve this problem, a greater knowledge of factors which regulate the differentiation of donor T cells toward cytotoxic or regulatory cells is necessary. We report that the β2-adrenergic receptor (β2-AR) is critical for regulating this differentiation, and that its manipulation can control aGvHD without impairing the graft-versus-tumor (GvT) effect. Donor T cell β2-AR expression and signaling is associated with decreased aGvHD when compared to recipients of β2-AR-/- donor T cells. We determined that β2-AR activation skewed CD4+ T cell differentiation in vitro and in vivo toward regulatory T cells (Tregs) rather than the T helper 1 (Th1) phenotype. Treatment of allo-HCT recipients with a selective β2-agonist, (bambuterol) ameliorated aGvHD severity. This was associated with increased Tregs, decreased cytotoxic T cells, and increased donor bone marrow-derived myeloid derived suppressor cells (MDSCs) in allogeneic and humanized xenogeneic aGvHD models. β2-AR signaling resulted in increased Treg generation through glycogen synthase kinase-3 activation. Bambuterol preserved the GvT effect by inducing NKG2D+ effector cells and central memory T cells. These data reveal how β-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.