Housing temperature-induced stress is suppressing murine GVHD through β2-adrenergic receptor signaling

摘要

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation (alloHCT), a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow (BM) 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 BM-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at IACUC mandated, cool standard temperatures (~22°C) are more resistant to developing GVHD than 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 (β-AR) 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-AR signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.