Beta-2 adrenergic signaling in immune homeostasis and reconstitution

Project Summary
Neurotransmitters and hormones serve as a link between the nervous and immune systems. Among them,
norepinephrine and epinephrine are synthesized in the postganglionic neurons of the sympathetic nervous
system and the adrenal medulla. Upon release, they engage the β2-adrenergic receptor (β2AR) expressed on
immune cells. Notably, β2AR abnormal expression and gene polymorphisms are associated with several types
of autoimmune diseases. However, mechanisms by which β2AR signaling dysfunction contribute to these
diseases remain largely unknown. In this context, our studies with mouse models have uncovered previously
unappreciated major dichotomous roles of β2AR in immune development and reconstitution: 1) Under specific
pathogen free (SPF) condition, β2AR deficiency causes significantly reduced T cell development in thymus in
contrast to increased CD115+ myeloid cell development in bone marrow (BM); 2) Both thymic and myeloid
development phenotypes are remarkably more manifested during immune reconstitution following allogeneic
hematopoietic cell transplantation (allo-HCT); 3) β2AR plays differential roles in in mature peripheral T cell
subsets and myeloid cell subsets that result in different outcome in graft-versus-host disease (GVHD). Together,
these findings highlight the critical and fundamental role of β2AR signaling in maintaining immune homeostasis
and regulating immune response. Therefore, this study will pursue three specific aims to test an overarching
hypothesis that β2AR signaling regulates immune development and reconstitution via cross-talking with
canonical immune signaling pathways and/or fine-tuning metabolic fitness of immune cells. Aim 1 will determine
mechanisms by which β2AR signaling regulates T cell development, reconstitution and GVHD. Aim 2 will define
mechanisms by which β2AR signaling regulates CD115+ myeloid cell development, reconstitution and GVHD.
Aim 3 will study the translational potential and mechanisms of pharmacologic β2AR intervention. We will use
unbiased RNA-seq transcriptomic approach along with flow cytometry, CyTOF mass cytometry and Seahorse
metabolic assay combined with cell type-specific β2AR knockout (Cre-LoxP) to define the molecular mechanisms
for T cell and myeloid cell differentiation and function. In the setting of allo-HCT, we will also examine the impact
of these mechanisms on GVHD and GVT effect. This project will not only improve our understanding of the
fundamental mechanisms of β2AR signaling in adaptive and innate immune cells in central and peripheral
immune organs, but it may also explain how β2AR signaling contributes to immunologic disorders and allo-HCT
based immunotherapy. Therefore, this study may have important ramifications on therapeutic rationale based
upon manipulation of β2AR signaling. Since β2AR agonists and antagonists are already widely available, new
clinical trials emanating from this research could be rapidly implemented for patients receiving allo-HCT for
treatment of blood cancers, or other hematologic or immunologic diseases in which allo-HCT can be curative.

Grant Number: 5R01HL159973-04
NIH Institute/Center: NIH
Principal Investigator: Xuefang Cao