ß2-Adrenergic receptor activation on donor cells ameliorates acute GvHD.
JCI Insight
; 5(12)2020 06 18.
Article
em En
| MEDLINE
| ID: mdl-32437333
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 ß2-adrenergic receptor (ß2-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 ß2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of ß2-AR-/- donor T cells. We determined that ß2-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 ß2-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. ß2-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 ß-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ativação Linfocitária
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Linfócitos T Reguladores
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Receptores Adrenérgicos beta 2
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Doença Enxerto-Hospedeiro
Limite:
Animals
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Humans
Idioma:
En
Revista:
JCI Insight
Ano de publicação:
2020
Tipo de documento:
Article