title: Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling.
abstract: Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼ 30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor-deficient (β2-AR(-/-)) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Leigh
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Kokolus
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Rachel E
authors.initials: RE
authors.lastname: O'Neill
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Jason W-L
authors.identifier: http://orcid.org/0000-0002-8219-2290
authors.initials: JW
authors.lastname: Eng
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Jingxin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors.forename: George L
authors.initials: GL
authors.lastname: Chen
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors.forename: Philip L
authors.initials: PL
authors.lastname: McCarthy
authors.affiliation: Department of Immunology and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: J David
authors.initials: JD
authors.lastname: Farrar
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; xuefang.cao@roswellpark.org elizabeth.repasky@roswellpark.org.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; xuefang.cao@roswellpark.org elizabeth.repasky@roswellpark.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology*
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D018343:Receptors, Adrenergic, beta-2