TY - JOUR AU - Mohammadpour, Hemn AU - Sarow, Joseph L. AU - MacDonald, Cameron R. AU - Chen, George L. AU - Qiu, Jingxin AU - Sharma, Umesh C. AU - Cao, Xuefang AU - Herr, Megan M. AU - Hahn, Theresa E. AU - Blazar, Bruce R. AU - Repasky, Elizabeth A. AU - McCarthy, Philip L. T1 - β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD PY - 2021/01/20/ AB - 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 that regulate the differentiation of donor T cells toward cytotoxic cells or Tregs 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 with recipients of β2-AR–/– donor T cells. We determined that β2-AR activation skewed CD4+ T cell differentiation in vitro and in vivo toward 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 BM–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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.137788 VL - 5 IS - 12 UR - https://doi.org/10.1172/jci.insight.137788 PB - The American Society for Clinical Investigation ER -