Vol. 53, Issue 4, 487-526, December 2001

Norepinephrine and 2-Adrenergic Receptor Stimulation Regulate CD4⁺ T and B Lymphocyte Function in Vitro and in Vivo

Adam P. Kohm and Virginia M. Sanders¹

Department of Cell Biology, Neurobiology, and Anatomy (A.P.K., V.M.S.), and Department of Microbiology and Immunology (V.M.S.), Loyola University, Stritch School of Medicine, Maywood, Illinois

I. Background
    A. Adaptive/Acquired Immunity
    B. Bidirectional Communication Between the Nervous and Immune Systems
    C. Norepinephrine and the 2-Adrenergic Receptor
II. Evidence and Mechanisms for the Release of Norepinephrine in Lymphoid Organs
    A. Lipopolysaccharide- and Antigen-Induced Norepinephrine Release
        1. Infection/Endotoxin.
        2. Particulate Antigens/Sheep Red Blood Cells.
        3. Soluble Protein Antigen.
    B. Cytokine Receptor Expression on Nerves
    C. Afferent Splenic Innervation
    D. Cytokine-Induced Norepinephrine Release
III. -Adrenergic Receptor Expression on CD4⁺ T and B Lymphocytes
    A. CD4⁺ T Lymphocytes
        1. Receptor Expression.
        2. Mechanisms Regulating Differential Receptor Expression on CD4⁺ T Cell Subsets.
    B. B Lymphocytes
IV. Effects on CD4⁺ T Lymphocytes
    A. 2-Adrenergic Receptor Signaling Components
    B. Proliferation, Differentiation, and Cell Trafficking
        1. In Vitro Proliferation and Differentiation.
        2. In Vivo Proliferation and Cell Trafficking.
    C. In Vitro and In Vivo Cell Surface Molecule Expression
    D. T Cell Cytokine Production
        1. In Vitro Th1-Like Cytokines.
        2. In Vitro Th2-Like Cytokines.
        3. In Vivo Cytokine Production.
        4. Differential Effects on Th1 versus Th2 Cytokines.
V. Effects on B Lymphocytes
    A. 2-Adrenergic Receptor Signaling Components
    B. B Cell Proliferation
    C. B Cell Surface Molecule Expression and Function
        1. In Vitro Surface Molecule Expression and Function.
        2. In Vivo Surface Molecule Expression.
    D. B Cell Differentiation and Antibody Production
        1. In Vitro Direct Alterations Induced by Elevations in Intracellular cAMP.
        2. In Vitro 2-Adrenergic Receptor Stimulation.
        3. In Vivo B Cell Differentiation and Antibody Production.
VI. Disease- and Health-Specific Implications
Acknowledgements
References

Historically, norepinephrine and the sympathetic nervous system have been associated with the "fight or flight" response, and they also contribute to the regulation of autonomic activity within the body, such as cardiovascular function. In addition, evidence over the past 30 years suggests that norepinephrine may also regulate the function of immune cells that protect the body against pathogens. The presence of sympathetic nerve fibers and the release of norepinephrine within lymphoid organs represent a mechanism by which signals from the central nervous system may influence immune cell function. The T cell-dependent antibody response is essential to successful host defense against numerous environmental pathogens. It is during this response that CD4⁺ T and B lymphocytes are activated to produce cytokines and antibody, respectively, leading to immune competence and protection. The goal of this review is to discuss the evidence supporting the release of norepinephrine within lymphoid organs and the expression of the 2-adrenergic receptor by CD4⁺ T and B lymphocytes. We also discuss the mechanisms by which 2-adrenergic receptor stimulation affects the level of cytokine and antibody produced by these cells both in vitro and in vivo. In cases where conflicting findings have been reported, we discuss potential variables that may have contributed to these conflicting findings. To conclude, we discuss the disease- and health-specific implications of the basic research being done in the area of sympathetic nervous system regulation of T and B lymphocyte function.