Blockade of Host ß2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs.
J Immunol
; 200(7): 2479-2488, 2018 04 01.
Article
em En
| MEDLINE
| ID: mdl-29445008
ABSTRACT
Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that ß2-adrenergic receptor (ß2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a ß2AR blocker significantly increases the GVT effect of donor CD8+ T cells by decreasing tumor burden without increasing graft-versus-host disease. ß2AR-deficient host mice have significantly increased effector memory and central memory CD8+ T cells and improved reconstitution of T cells, including CD4+Foxp3+ regulatory T cells. Notably, ß2AR deficiency induces increased CD11c+ DC development. Also, ß2AR-deficient bone marrow-derived DCs induce higher CD8+ T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that ß2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host ß2AR signaling in suppressing T cell reconstitution and GVT activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Dendríticas
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Receptores Adrenérgicos beta 2
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Transplante de Células-Tronco Hematopoéticas
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Linfócitos T CD8-Positivos
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Neoplasias Hematológicas
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Efeito Enxerto vs Tumor
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Antagonistas de Receptores Adrenérgicos beta 2
Limite:
Animals
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2018
Tipo de documento:
Article