Norman Cousins Lecture
The beta2-adrenergic receptor on T and B lymphocytes: Do we understand it yet?

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Abstract

The role played by the beta2-adrenergic receptor (β2AR) in regulating the level of T and B lymphocyte function has been studied for over half a century. During this time, we have learned that T and B lymphocytes express almost exclusively the β2AR, and that the level of expression on a specific lymphocyte subset differs due to epigenetic regulation by histone and DNA methylation. We have also learned that engagement of the β2AR on lymphocytes, by either norepinephrine or a selective pharmacologic ligand, regulates the level of lymphocyte activity differentially, depending on the time of receptor engagement in relation to the activation and differentiation state of the cell, the molecular signaling pathway activated, and the cytokine microenvironment. The challenge now is to determine if we understand enough about how this receptor functions on lymphocytes to predict the relevance of such regulation to overall immune homeostasis and the development/progression of human disease.

Highlight

► Various mechanisms are responsible for the regulation of T and B lymphocyte activity and function following beta2-adrenergic receptor engagement.

Introduction

It was Norman Cousins who challenged all of us to determine the mechanism by which he survived two major illnesses, ankylosing spondylitis, and a near-fatal heart attack, simply by harnessing the power of human emotions. When he was taken to the hospital for the heart attack, he said, “…I want you to know that you’re looking at the darnedest healing machine that’s ever been wheeled into this hospital”. He believed that the mind and body were connected somehow and that each could help the other to heal. Exactly how this communication occurred to bring about healing was a mystery to him, but he knew it was real and that an understanding of the mechanism would lead to cures that were unimaginable. For the past 50 years, a number of researchers have accepted this challenge to study this connection between the mind and body, in particular, to determine the mechanism responsible for mediating the effect on health.

A fine balance exists in the body to maintain health and overall homeostasis. This balance is maintained by the proper functioning of every organ system. One participant in this balance equation involves the immune system, which evolved to protect us not only from the environment around us, which is filled with infection-causing microorganisms, allergens, and cancer-promoting agents, but also from the environment within us, which can develop transformed cells that cause cancer and autoimmune disease (Fig. 1). It is essential that a mechanism exists to coordinate these organ systems to respond immediately to a threat and to bring the organ systems back to normal after the crisis subsides. One key mechanism responsible for such coordination involves the autonomic nervous system, which serves as the messenger from the mind to the body for all organ systems, including the immune system (Fig. 2; Ader et al., 1990, Nance and Sanders, 2007). Another key mechanism responsible for such coordination involves cytokines, which serve as the messenger to the brain from the activated immune cells that are responding to an external or internal threat (Besedovsky et al., 1983). These two mechanisms of communication between the brain and immune system are now known to play a major role in maintaining a protective balance in the body to maintain health and homeostasis.

Section snippets

Expression of the β2AR on T and B lymphocytes

The autonomic nervous system is composed of two distinct systems, namely the sympathetic and parasympathetic nervous systems that secrete norepinephrine and acetylcholine, respectively. The parenchyma of lymphoid organs are innervated primarily by sympathetic nerve fibers that release norepinephrine within hours of antigen recognition by immune cells (Felten et al., 1985). The released norepinephrine binds to either alpha- or beta-adrenergic receptors that are expressed by immune cells,

Effect of β2AR engagement on CD4+ T cell function

The effect of β2AR engagement on an activated naïve CD4+ T cell vs. an effector Th1 cell was found to be dependent on different factors. β2AR engagement on an activated naïve T cell cultured in the presence of IL-12 induced more IFN-γ to be produced in comparison to naïve cells activated alone without β2AR engagement (Fig. 4; Swanson et al., 2001). This increase in IFN-γ was due to a higher level of IFN-γ being secreted per cell by the resulting Th1 cells that developed, as opposed to more Th1

Potential clinical relevance for differential β2AR expression on CD4+ T cells

Does this mean that these findings cannot be translated clinically? The answer is that they will be translatable after we understand more about the mechanisms responsible for these differences so that we can apply these findings to clinical situations in a rational manner. For example, diseases that appear to be mediated by changes in either Th1 cell IFN-γ production, including autoimmune diseases such as multiple sclerosis, and infectious diseases such as those caused by viruses, might be

Effect of β2AR engagement on B cell function

Interestingly, the lack of β2AR expression on a Th2 cell provided a means to determine the direct effect of β2AR engagement on a B cell involved in a Th2 cell-dependent IgG1 or IgE response, without the complication of a simultaneous direct effect on the Th2 cell (Fig. 6). Although a number of reports exist as to the effect of β2AR ligand exposure on a T cell-dependent antibody response (Kohm and Sanders, 2001), the mechanism by which β2AR engagement directly affected either T or B cell

Mechanism for the β2AR-induced upregulation of CD86 and IgG1 in B cells

In the resting state, B cells express a very low level of CD86, which increases after antigen exposure and crosslinking of the B cell receptor. A β2AR agonist was also found to increase CD86 expression on B cells and, in combination with antigen, increased CD86 expression in an additive manner (Kasprowicz et al., 2000, Kohm et al., 2002). The relevance of this effect was shown in vivo using the norepinephrine-depleted antigen-specific adoptive transfer model (Kohm et al., 2002). In these mice,

Potential clinical relevance for the β2AR-induced upregulation of CD86 and IgG1 in B cells

These findings will be translatable after we understand more about the mechanisms responsible for these differences so that we can apply these findings to clinical situations in a rational manner. For example, the level of antibody produced in vivo by a B cell in response to a T cell-dependent antigen is critical for providing protection against pathogens and assuring host survival. One report has shown that the level of antibody produced by individuals immunized with S. pneumoniae positively

Mechanism for the β2AR-induced upregulation of IgE in B cells

During a Th2-dependent response, some B cells will switch to IgG1 and some to IgE, which is the antibody isotype that contributes to the development of allergy and asthma. Engagement of the β2AR on an activated B cell in the presence of IL-4 leads to an increase in IgE that is cAMP and PKA-dependent. As opposed to the β2AR-induced increase in IgG1, which is also cAMP and PKA-dependent, the increase in IgE is not dependent on CREB activation, but is dependent on the activation of p38MAPK (

Potential clinical relevance for β2AR-induced upregulation of IgE in B cells

The clinical application for these findings relate primarily to conditions of allergy and allergic asthma, which are both linked to an increase in IgE. Not only does β2AR engagement on a B cell occur when norepinephrine is released in response to allergens under normal physiological conditions, but also the released norepinephrine participates in the generation of a normal level of IgE and lung pathology, as evidenced in mice depleted of norepinephrine prior to antigen exposure (Pongratz et

Summary

In summary, the role played by the β2AR in regulating the level of T and B lymphocyte function is difficult to summarize simply because the mechanisms involved in mediating the effects are different and complex. The challenge now is to determine if we understand enough about how this receptor functions on T and B lymphocytes to predict the relevance of such regulation to overall immune homeostasis and the development/progression of human disease. Norman Cousins wrote in his book Anatomy of an

Acknowledgments

I am forever indebted to the dedication of the graduate and postdoctoral trainees, as well as my esteemed colleagues and collaborators, who have participated in the research presented in this article. Without them, as well as the generous funding from the NIH (AI37326 and AI47420), none of these discoveries would have been possible.

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