β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD
PublisherThe American Society for Clinical Investigation
MetadataShow full item record
AbstractAcute 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.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85086747266&doi=10.1172%2fjci.insight.137788&partnerID=40&md5=d38e356034ab5112f1ac056ec4e07d0d; http://hdl.handle.net/10713/13182
- HIF-1α inhibitor echinomycin reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect.
- Authors: Yao Y, Wang L, Zhou J, Zhang X
- Issue date: 2017 Feb 10
- Cytotoxicity of Donor Natural Killer Cells to Allo-Reactive T Cells Are Related With Acute Graft-vs.-Host-Disease Following Allogeneic Stem Cell Transplantation.
- Authors: Sheng L, Mu Q, Wu X, Yang S, Zhu H, Wang J, Lai Y, Wu H, Sun Y, Hu Y, Fu H, Wang Y, Xu K, Sun Y, Zhang Y, Zhang P, Zhou M, Lai B, Xu Z, Gao M, Zhang Y, Ouyang G
- Issue date: 2020
- Notch pathway plays a novel and critical role in regulating responses of T and antigen-presenting cells in aGVHD.
- Authors: Luo X, Xu L, Li Y, Tan H
- Issue date: 2017 Apr
- [The role of CD4+ CD25+ T cell and FOXP3 in hsot acute graft rejection].
- Authors: Liu YJ, Wu DP, Li CX, He J, Qiu QC, Zhang XG
- Issue date: 2006 Oct