Essential roles of CD27/CD70 co-stimulation and β2- adrenergic receptor signaling in suppressing GVHD
Leigh, Nicholas Davis
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Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic disorders. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage the genetically distinct normal host tissue. Current strategies to limit GVHD include the pre- or post-transplantation depletion of T cells or therapies aimed at decreasing T cell function. Unfortunately, these therapies are broadly immunosuppressive, which dampens the beneficial graft versus tumor effect and infectious immunity provided by T cells. In addition, GVHD that is refractory to first line therapies has mortality rates as high as 90%, making new more efficacious and targeted therapies needed. To better control GVHD, it is essential to understand the biological mechanism of GVHD. To this end, my project aimed to decipher two molecular pathways that are involved in GVHD pathogenesis. Herein, I focus on the role of CD27/CD70 co-stimulation in GVHD and also present findings that link the adrenergic stress response to GVHD severity. With the goal of finding novel strategies to decrease GVHD, I wanted to target T cell co-stimulation, more specifically CD27/CD70 co-stimulation, to decrease GVHD. This interaction has been shown to be essential for optimal T cell responses. My findings suggest a surprising role for CD27/CD70 T cell co-stimulation, which counter to expectations has the ability to suppress GVHD. I show that antibody blockade of this interaction or the genetic elimination of donor T cell-derived CD27 or host-derived CD70 all result in significantly increased GVHD. Increased GVHD in CD70 −/− hosts is accompanied by a significant increase in the pro-inflammatory cytokines IFN-γ, IL-17, IL-2, and TNF-α. My findings indicate that the absence of CD27/CD70 co-stimulation increases T cell expansion. Increased expansion in CD70 −/− hosts is due to a decrease in caspase-8 mediated activation induced cell death of donor T cells. Absence of host-derived CD70 also results in increased accumulation of donor effector T cells. Together, my data indicate that CD27/CD70 T cell co-stimulation is an essential suppressor of allogeneic T cell responses, and suggest that targeting this interaction with agonistic antibody may be a feasible strategy for the amelioration of GVHD. We have also discovered a previously unknown role for the adrenergic stress response in GVHD. During the course of studies evaluating the role of ambient housing temperature on GVHD severity, we made the fortuitous discovery that adrenergic receptor signaling decreases GVHD. Previous studies showing an immunosuppressive effect of housing mice at 22°C, the standard temperature in which mice are housed, prompted us to compare GVHD in mice housed at 22 and 30°C. An ambient temperature of 30°C is the thermoneutral temperature for mice, a temperature that eliminates the need for norepinephrine mediated adaptive thermogenesis. We have found that the addition of a commonly used β-blocker, propranolol, significantly increases GVHD following allo-HCT when mice are housed at 22°C. This suggests that norepinephrine has immunosuppressive effects in mice housed at 22°C. Further, we have found that β 2 -, but not β 1 -, adrenergic receptor signaling is responsible for norepinephrine-mediated suppression of GVHD. More importantly, we can decrease GVHD with the addition of a β 2 -adrenergic receptor (β 2 -AR) agonist. Studies using β 2 -AR −/− mice indicate that host-derived β 2 -adrengeric receptor signaling is essential for controlling GVHD. This study suggests that treating patients with β-blockers post allo- HCT should be done with caution, and that β 2 -agonist treatment may have potential for decreasing GVHD. These findings describe essential roles for host-derived immunosuppression in GVHD.