IntroductionThe central and peripheral nervous systems can modulate immune function by releasing soluble factors such as hormones, neuropeptides, and neurotransmitters. 1,2 Serotonin (5-HT) is a classical neurotransmitter and vasoactive amine best known for its role in the regulation of variety of physiologic states and behaviors, including pain, appetite, mood, and sleep. 3 Despite these major roles for 5-HT in the central nervous system, the vast majority of 5-HT is produced in the periphery (Ͼ 90%), primarily by enterochromaffin cells in the gut. 4 Consistent with its abundance in the periphery, 5-HT is recognized as an important inflammatory mediator with significant immune-modulatory effects. 2,5 Mast cells and platelets both express the 5-HT specific transporter (SERT) which enables them to sequester 5-HT from the microenvironment. In turn, 5-HT is released in response to injury and/or inflammatory signals such as platelet activating factor, complement components (C3a and C5a), and IgE complexes. 5,6 Released 5-HT has been shown to regulate platelet aggregation 7 and to promote the accessory function of macrophages, and it is a potent eosinophil chemoattractant. 8,9 Consistent with these effects, 5-HT is implicated in the pathogenesis of inflammatory disorders, including asthma, inflammatory bowel syndrome, allergic diarrhea, and chronic eczema. 5,[10][11][12][13][14] Several studies have demonstrated that T and B lymphocytes are functionally responsive to 5-HT, implicating a role for this monoamine in the generation of adaptive immune responses. Inhibition of endogenous 5-HT synthesis can impair rodent T-cell proliferation. 2,15,16 Conversely, exogenous 5-HT is reported to suppress T-cell proliferation. 3 5-HT triggers the increased release of preformed IL-16 from CD8 ϩ T cells and can initiate delayedtype hypersensitivity reactions through the local recruitment and activation of CD4 ϩ T cells. [17][18][19] Thus, the precise role of 5-HT in modulating lymphocyte activation or function is currently ambiguous. Moreover, the identity of 5-HTRs expressed by T cells and the intracellular signaling pathways that transduce this signal remain unclear. 5-HTR signaling is complex with 7 recognized receptor subfamilies. 2 With the exception of the 5-HT 3 receptor, which is a ligand-gated ion channel, they belong to the family of 7 transmembrane G protein-coupled receptors. Both 5-HT 1 and 5-HT 2 receptor subfamilies have been implicated in signaling T cells. 3,[15][16][17]20,21 With rare exception, however, 20 most studies have only demonstrated the expression of 5-HTR gene transcripts or pharmacologic sensitivity to 5-HTR agonists or antagonists. 3 To elucidate the function of 5-HT signaling in T cells, we have made a comprehensive analysis of 5-HTR expression and signaling in primary mouse T cells. We show that naive T cells primarily express the 5-HT 7 receptor. Exogenous 5-HT leads to rapid phosphorylation of extracellular signal related kinase-1 and -2 (ERK1/2) and IB␣ in bulk naive T cells, early steps that ar...

IntroductionDendritic cells (DCs) are highly specialized to integrate diverse stimuli for the generation of antigen-specific immunity and lifelong immunologic memory. As immature cells, they are ubiquitously distributed in peripheral tissues where they serve as immune sensors, sampling foreign and self antigens. 1,2 Microbial antigens recognized by pattern recognition receptors, 3 and self molecules released by dead and dying cells, 4 trigger the migration of DCs. While en route to secondary lymphoid tissues, DCs up-regulate their expression of cell surface major histocompatibility complex (MHC) and costimulatory molecules and the secretion of cytokines and chemokines necessary for the initiation of adaptive immune responses. 1,2 The intimate and dynamic interactions that occur between DCs and cognate lymphocytes in secondary lymphoid tissues are equally specialized. It is now clear that T-cell activation requires a zone of adhesive, direct contact with antigen-presenting cells (APCs), popularly known as the immune synapse. 5 From the DC vantage, the formation of immune synapses involves cytoskeletal reorganization and the focal redistribution of antigen-MHCs and accessory molecules. [6][7][8][9] The immune synapse appears to maximize the physical interactions between DCs and lymphocytes and forms a stable platform for the recruitment and concentration of signaling molecules. 10,11 The immune synapse exhibits many similarities with classical neuronal synapses, including a requirement for cell-to-cell adhesion and close membrane apposition. In addition, triggering of cell surface receptors leads to intracellular signal transduction in both structures. 10,11 The tight synaptic cleft between neurons (20-40 nm) and the neuromuscular junction (ϳ100 nm) facilitates the rapid diffusion of neurotransmitters. 11 Although a relatively transient structure, the immune synapse also features a synaptic cleft (15-40 nm). 9,10,12 We therefore considered the possibility that the immune synapse may also support the regulated secretion of labile molecules that could contribute to signaling between DCs and lymphocytes.Langerhans cells, the archetypal DCs, are known to accumulate neurotransmitters. 13 ) is a classical neurotransmitter and vasoactive amine involved in signaling a variety of behavioral and physiologic states including appetite, sleep, mood, and pain. 14 Moreover, 5-HT has significant effects on inflammation and immunity. Mast cells and platelets both express the 5-HT-specific transporter (SERT), which enables them to sequester 5-HT from the microenvironment. In turn, this 5-HT is released in response to injury or inflammatory signals such as IgE complexes, complement components, and platelet-activating factor. 15,16 Exocytosed 5-HT regulates platelet aggregation and modulates leukocyte motility and airway hyperresponsiveness. 16,17 5-HT is also reported to modulate T-cell activation and differentiation. 16,18,19 The mechanisms by which T cells may encounter For personal use only. on May 12, 2018. by guest www.bloodjou...

These data reveal coordinated changes in 5-HT production, metabolism and storage that may optimize 5-HT secretion from the CD8(+) T cell subset in response to activation stimuli.