ommunication between the neuroendocrine and immune systems is commonly associated with release of humoral factors such as cortisol and epinephrine from the hypothalamicpituitary-adrenal (HPA) axis 1,2 (Fig. ). However, it was anticipated that a neuronal control system also plays an important role in communication 2,3 . It has been known for over a century that transcutaneous electrical stimulation of the enlarged spleen in patients with leukaemia leads to a reduction of organ size and an increase in blood leukocyte counts 4 . These experiments suggested a functional innervation of the spleen, and in the 80s, immunohistochemical studies demonstrated the close association of autonomic nerve terminals with macrophages and lymphocytes (reviewed in Ref. ). The morphology of these contacts is indicative of a chemically mediated transmission between nerves and immune cells (Fig. ).
In this article, we examine whether the criteria for chemically mediated transmission between nerve terminals and immune cells in lymphoid organs are met (see Box 1). The local regulation of the nerve-immune cell dialogue will be outlined taking splenic interleukin 6 (IL-6) production as an example. Finally, the significance of the dialogue for the development of immune responses is discussed.
The association between nerve terminals and immune cells in the spleen
Neurotransmitter synthesis, storage and release
In the splenic nerve, for example, norepinephrine (NE) is synthesized and stored in the nerve terminal 6 (Fig. ). Neuropeptides, such as neuropeptide Y (NPY) (Ref. 7), are synthesized in the soma of splenic nerves, transported via the axon, and are also stored in the nerve terminal. NE, NPY and opioids are produced in the same nerve and are colocalized in the nerve terminal 8 . Furthermore, in immunohistochemical studies acetylcholine (not in the spleen), calcitonin gene-related peptide (CGRP), somatostatin, substance P and vasoactive intestinal peptide (VIP) were detected in lymphoid organs .
In vivo microdialysis studies have demonstrated significant NE release from the spleen . In situ perfusion studies of the porcine spleen with electrical stimulation of the postganglionic splenic nerves led to the efflux of NE and NPY (Ref. 7). In addition, in vitro superfusion experiments using spleen slices demonstrated neural release of NE (Refs 9-11) and endogenous opioid peptides . All these techniques demonstrated inducible NE release in a similar way, which indicates that slice superfusion is as valid as in vivo or in situ methods. Although transmitters other than NE, NPY or opioids were not analyzed in these experiments, it is very likely that other neuropeptides such as CGRP, somatostatin, substance P and VIP in the nerve fibres of lymphoid organs are also released. In less than 1% of cases (E. Weihe, pers. commun.), nerve endings terminate at immune cells forming a small cleft of less than 10 nm (Ref. 3). Upon release, the transmitters diffuse to target immune cells in the local microenvironment and bind to specific surface receptors, thus leading to chemically mediated transmission.