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β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD
Hemn Mohammadpour, … , Elizabeth A. Repasky, Philip L. McCarthy
Hemn Mohammadpour, … , Elizabeth A. Repasky, Philip L. McCarthy
Published May 21, 2020
Citation Information: JCI Insight. 2020;5(12):e137788. https://doi.org/10.1172/jci.insight.137788.
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Research Article Immunology Transplantation

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

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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.

Authors

Hemn Mohammadpour, Joseph L. Sarow, Cameron R. MacDonald, George L. Chen, Jingxin Qiu, Umesh C. Sharma, Xuefang Cao, Megan M. Herr, Theresa E. Hahn, Bruce R. Blazar, Elizabeth A. Repasky, Philip L. McCarthy

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Figure 2

Expression of β2-ARs on T cells regulates the T cell phenotype during allogeneic responses.

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Expression of β2-ARs on T cells regulates the T cell phenotype during al...
(A) Immune-related gene expression in WT or β2-AR–/– CD4+ T cells sorted from spleen at day 14 after allo-HCT in the B6→BALB/c model transplanted with 3.5 × 106 WT C57BL/6 TCD-BM alone or combined with 0.7 × 106 WT C57BL/6 or β2-AR–/– pan–T cells using NanoString nCounter Immunology Panel mRNA microarray (splenocytes pooled from 5–6 mice before CD4+ T cell sorting). (B) RORγt+T-bet+ frequencies in liver and spleen CD4+ T cells within single live H-2b+H-2d–CD45+CD3+ cells 7 and 14 days after allo-HCT. There are increased RORγt+T-bet+CD4+ T cells in recipients of β2-AR–/– T cells. Representative plots are shown from 2 independent experiments (n = 5–6 in total). (C) T-bet+, Foxp-3+, IFN-γ+, IL-17+, and IL-10+ frequencies in CD4+ T cells within single live H-2b+H-2d–CD45+CD3+ cell populations from the spleen and liver at days 7 and 14, and the GI tract 14 days after allo-HCT. Data pooled from 2 individual experiments, total n = 5–6 per group. B6→BALB/c model using B6→BALB/c model transplanted with 3.5 × 106 WT C57BL/6 TCD-BM alone or combined with 0.7 × 106 WT C57BL/6 or β2-AR–/– pan–T cells. CD4+T-bet+, CD4+IFN-γ+, CD4+IL-17+, and T-bet+Rorγt+CD4+ T cells were significantly increased in β2-AR–/– versus WT T cells. CD4+Foxp-3+ and CD4+IL-10+ cells significantly increased in WT versus β2-AR–/– T cells. (D) Plasma levels of inflammatory/inhibitory cytokines of irradiated BALB/c mice transplanted with TCD-BM plus WT or β2-AR–/– T cells at 7 and 14 days. Plasma IFN-γ on days 7 and 14 and IL-17 levels on day 7 increased significantly, while IL-4 and IL-10 levels decreased significantly in β2-AR–/– T cell recipients. There were no differences in plasma GM-CSF levels. For comparison of the means, an unpaired 2-tailed t test was used in B, C, and D. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as median ± min to max.

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