The emergence of neurotransmitters as immune modulators Rafael Franco 1 , Rodrigo Pacheco 2 , Carmen Lluis 1 , Gerard P. Ahern 3 and Peta J. O’Connell 4 1 Institut d’Investigacions Biome ` diques August Pi i Sunyer (IDIBAPS) and Department of Biochemistry and Molecular Biology, Faculty of Biology, Diagonal 645, University of Barcelona, 08028 Barcelona, Spain 2 Millennium Nucleus on Immunology and Immunotherapy, Department of Microbiology and Molecular Genetics, Faculty of Biological Sciences, Pontificia Universidad Cato ´ lica de Chile, Alameda 340, Santiago E-8331010, Chile 3 Georgetown University, 3900 Reservoir Rd, Washington DC 20007, USA 4 Robarts Research Institute and the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada Initially, the idea that neurotransmitters could serve as immunomodulators emerged with the discovery that their release and diffusion from nervous tissue could lead to signaling through lymphocyte cell-surface receptors and the modulation of immune function. It is now evident that neurotransmitters can also be released from leuko- cytes and act as autocrine or paracrine modulators. Here, we review the data indicating that leukocytes synthesize and release ‘neurotransmitters’ and we also discuss the diverse effects that these compounds exert in a variety of immune cells. The role of neurotransmitters in immune- related diseases is also reviewed succinctly. Current and future developments in understanding the cross-talk be- tween the immune and nervous systems will probably identify new avenues for treating immune-mediated dis- eases using agonists or antagonists of neurotransmitter receptors. Cross-talk between the nervous system and the immune system Cytokines and other molecules released in the central nervous system (CNS) by activated cells of the immune system can influence neurotransmission [1]. It now seems that neurotransmitters also exert a considerable and reci- procal influence on the function of the immune system. Leukocytes express receptors for the main brain neuro- transmitters, such as glutamate, dopamine, acetylcholine (ACh) and serotonin (5-HT), providing strong evidence for their role as immune modifiers. Exploring the direct mech- anisms by which the immune and the nervous systems communicate holds great promise, not only for understand- ing how the entire organism operates in health, but also for developing novel therapeutic strategies for both neurologi- cal and immune-mediated diseases. Neurotransmitters derived from sources outside of the immune system, for example, from gut enterochromaffin cells or autonomic nerves that innervate lymphoid organs, can initiate or modify leukocyte signal transduc- tion directly (Figure 1). In addition, the brain can influence immune function powerfully through the hypothalamic–pituitary–adrenal axis and the release of corticosteroids [2]. Consistent with this, immune compe- tence is impaired in hypophysectomized (surgical removal of the pituitary gland) animals and restored by adminis- tration of growth hormone and prolactin, which both have potent immunoregulatory effects [3,4]. The neurotransmit- ters dopamine and glutamate interact directly with T-cell- expressed receptors, leading to the activation or suppression of various T-cell functions, including cytokine secretion, proliferation and integrin-mediated adhesion and migra- tion (reviewed in [5–9]). Corticosteroids released from sympathetic nerves or the adrenal gland have profound immunosuppressive effects on the lymphoreticular system, inhibiting many effector functions of lymphocytes and macrophages and disrupting their trafficking patterns [10]. Elevated plasma norepinephrine and epinephrine con- centrations that accompany stress produce changes in lymphocyte and monocyte function [11]. Interestingly, there are exceptions to this general trend and a good example is given by histamine; although a CNS neurotransmitter, histamine is released mainly by mast cells in the periphery (not by nerves) and has a fundamental role in innate immu- nity. In this review, we consider recent studies showing that classical neurotransmitters are synthesized and released by lymphocytes and antigen-presenting cells (APCs) and can signal changes in immune function (immune-driven immu- nity, Figure 1) directly. A new paradigm: leukocytes produce and/or release neurotransmitters Several recent studies have revealed that key players in the generation of adaptive immune responses, dendritic cells (DCs) and lymphocytes, are capable of synthesizing and/or releasing classical neurotransmitters, including ACh, dopamine, 5-HT and glutamate. Fujii et al. provided the first evidence for ACh synthesis in T cells [12]. CD4 + T cells contain substantially more ACh compared with CD8 + T cells or B cells [13,14] and mitogens increase both the synthesis and release of ACh from lymphocytes [13]. These studies demonstrate that lymphocytes possess the essen- tial components for a non-neuronal cholinergic system and Review TRENDS in Immunology Vol.28 No.9 Corresponding author: Franco, R. (rfranco@ub.edu). Available online 6 August 2007. www.sciencedirect.com 1471-4906/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2007.07.005