?2-Adrenergic receptor activation on donor cells ameliorates acute GvHD.

ABSTRACT: 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 ?2-adrenergic receptor (?2-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 ?2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of ?2-AR-/- donor T cells. We determined that ?2-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 ?2-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. ?2-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 ?-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.

SUBMITTER: Mohammadpour H 

PROVIDER: S-EPMC7406296 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature