β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number137495
JournalJCI Insight
Volume5
Issue number12
DOIs
StatePublished - Jun 18 2020

Bibliographical note

Funding Information:
The authors thank Bonnie L. Hylander, Jeanne M. Prendergast, Samuel A. Ministero, Minhui Chen, and Guanxi Qiao for technical assistance and support, as well as the Genomics Shared Resource (Roswell Park), Translational Imaging Shared Resource, and the Roswell Park Flow Cytometry Core Facility for expert support. This project was supported by NIH (NIH) grants R01 CA205246 and R01 CA236390 (to ER); R37 AI34495, R01 HL118979, and R01 HL56067 (to BRB); F32 CA239356 (to HM); the Roswell Park Alliance Foundation and a donation from Brendan and Elise McCarthy (PM); and NCI grant P30CA016056.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Fingerprint Dive into the research topics of 'β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD'. Together they form a unique fingerprint.

Cite this