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 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.
Highlights
Allogeneic hematopoietic cell transplant is a potentially curative intervention for patients with hematological malignancies due to eradication of host malignant cells by donor T cells effect
Using major histocompatibility complex (MHC) and minor histocompatibility antigen mismatched HCT murine models, and a humanized NOD-scid IL-2Rγ–/– (NSG) model of acute graft-versus-host disease (GvHD) (aGvHD), we demonstrate that β2-adrenergic receptor (β2-Adrenergic receptors (ARs)) expression by allogeneic T cells regulates the differentiation of CD4+ T cells from T helper 1 (Th1)/Th17 to a Th2/Treg phenotype, ameliorating aGvHD without compromising GvT
That glycogen synthase kinase-3 (GSK-3) activity plays a role in regulating the immunosuppressive function of Tregs [36, 37] — and that β-AR stimulation has been shown to be dependent on GSK-3 activity in other cell types, like cardiomyocytes [38, 39] — we investigated whether β2-AR signaling increased induced Treg (iTreg) generation by modulating GSK-3 activity
Summary
Allogeneic hematopoietic cell transplant (allo-HCT) is a potentially curative intervention for patients with hematological malignancies due to eradication of host malignant cells by donor T cells (the graft-versus-tumor; GvT) effect. Using major histocompatibility complex (MHC) and minor histocompatibility antigen (miHA) mismatched HCT murine models, and a humanized NOD-scid IL-2Rγ–/– (NSG) model of aGvHD, we demonstrate that β2-AR expression by allogeneic T cells regulates the differentiation of CD4+ T cells from Th1/Th17 to a Th2/Treg phenotype, ameliorating aGvHD without compromising GvT. These data lead us to propose that selective β2-AR agonists may serve as potential therapeutic agents to attenuate aGvHD while preserving the GvT effect
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