Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands
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(2) 66 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. cells contributes to B cell activation and differentiation into antibody secreting plasma cells. T cell help is mediated by both soluble and membrane-bound molecules, such as cytokines and CD40-CD40L, respectively [5]. In addition, T cell derived cytokines can also promote or potentiate effector functions of other immune cells, such as macrophages, dendritic cells, and NK cells, thus promoting efficient elimination of invading pathogens or tumour cells [6]. Two main T cell subsets have been described, which may be phenotypically differentiated by expression on the cell surface of CD4 or CD8, which work as co-receptors for the MHC molecule. CD8+ and CD4+ T cells recognize Ags as peptides bound to class I and class II MHC molecules, respectively [7]. Effector CD8+ T cells may directly recognize tumour or infected cells expressing foreign Ags as surface pMHC complexes and subsequently they mediate killing of those cells by secreting cytotoxic granules containing toxic proteins, such as perforin and granzyme [8]. In addition, by secreting IFN-, cytotoxic CD8+ T cells may also potentiate function of other immune cells, including macrophages and Natural Killer (NK) cells [8]. Thus CD8+ T cells are key players during adaptive immune response against intracellular pathogens and tumours [7]. Despite often effector CD8+ T cells belong to type I cytotoxic IFN- secreting-T cells (Tc1), there is a secondary subset of CD8+ T cells, Tc2, which produce IL-4, IL-5 and IL-10 [9]. Whereas the Tc1 subset constitute a major defence against virus-infected cells [10, 11] and malignant cells [9], the Tc2 subset has been shown to participate during chronic human pathologies such as viral infections [12], cancer [13, 14], neurologic [15] and autoimmune diseases [16]. On the other hand, effector CD4 + T cells not only contribute to efficient activation of CD8+ T cells [17-19] and B cells [20], but they also regulate function of several cells of the innate arm of immune system, such as macrophages and NK cells. Depending on the signals that dendritic cells (DCs) provide to T cells in addition to antigenic pMHC, they can promote the differentiation of distinct CD4 + T cell subsets, including T helper 1 (Th1), Th2 and Th17 [21-23]. A Th1 phenotype on CD4+ T cells is favoured by the secretion of IL-12 by DCs. In contrast, a Th2 phenotype is induced in the absence of IL-12 secretion during Ag recognition on DCs [24]. Th1 cells secrete predominantly IFN- and they promote cellular immunity protecting against intracellular pathogens and tumour cells. In addition, IFN- favours secretion of Ig2a and IgG3 by Ag-specific B cells, both isotypes that efficiently couple Ag recognition with complement activation. In contrast, Th2 cells secrete mainly IL-4, which promote secretion of IgE by B cells, an isotype that couple the recognition of Ag with degranulation of mast cells. In addition, Th2 cells contribute to the activation of eosinophils, promoting allergic-type immune responses that can be efficient at eliminating extracellular pathogens, such as helmints and extracellular barcterium [25]. The Th17 phenotype has been more recently described which secrete mainly IL-17. Differentiation into Th17 is promoted by IL-23, TGF (in mouse) and IL-6, which can be secreted by DCs during Ag presentation. It is though that Th17 cells protect against extracellular bacteria, particulary in the gut [8], however they have also been extensively associated with autoimmune diseases [21]. Another type of CD4+ T cells consists of T. Pacheco et al.. regulatory (Treg) cells, which express the transcriptional factor FoxP3, secrete mainly IL-10 and suppress several of the effector function of Ag-specific T cells [7]. Due to their inhibitory properties, an exacerbated activity of Treg cells could impair T cell immunity and promote tumour development or persistence/dissemination of infectious agents in the organism. In constrast, a deficient activity of Treg cells could lead to uncontrolled activation and function of effector T cells and the onset of autoimmunity. 1.3. The T Cell-DC Synapse Defines the Nature of T Cell Response Triggered by Antigenic pMHC Dendritic cells (DCs) are the most potent APCs specialized in the initiation of adaptive immune responses by directing the activation and differentiation of naïve T lymphocytes [22, 23]. These cells can capture both self and foreign Ags in diverse tissues and, migrate to secondary lymphoid organs to present captured and processed Ags on MHC molecules to T cells [7]. The T cell-DC contact interface is a highly organized supramolecular structure, consisting of cell-surface receptors and associated-signalling proteins. The molecular rearrangements occurring at the T cell-DC interface is known as immunological synapse. This structure can be compared to the neurosynapse in the nervous system and soluble mediators accumulate in the narrow cleft between DC and T cell plasma membranes reaching high local concentrations [26]. T cell-DC synapses can comprise a diverse range of contact modes and distinct molecular arrangements that ultimately determine the nature of the T cell response [26, 27]. It is thought that the composition, duration, and frequency of immunological synapse contacts provide the integration of quantity and quality of the signalling that determines the nature of T cell function. Thus, DC-T cell interaction can control and regulate T cell activation, effector function, and induction of tolerance [26]. Important functional components of the immunological synapse are activating/inhibitory receptors pairs expressed either on the DC or the T cell surface [28-35]. Furthermore, the synapse recruits several modulating receptors that, upon engagement, contribute to polarization of effector T cell responses. The most significant intercellular molecular interactions mediating T cell-DC communications are described in the following sections. 1.3.1. TCR/pMHC Interaction The TCR/pMHC interaction determines the specificity of T cell activation and the nature of the cellular response mediated by these cells [36-39]. Recognition of pMHC by the TCR is required to trigger all the later signalling events occurring, during T cell function. The signaling pathways contributing to an efficient activation of T cells after specific Ag recognition include the PKC/Ca2+ pathway and the mitogenactivated-protein-kinases (MAPK) ERKs, JNKs and p38. All of these signaling molecules together promote the activation of transcriptional factors NF-B, NF-AT and AP-1 complexes. The simultaneous efficient turning on of all of these pathways leads to T cell activation with expansion of Agspecific T cell clones and differentiation into effector and memory cells. By evaluating the quality and quantity of the TCR signalling, we and others have shown that the half-life of TCR/pMHC interaction is a critical parameter regulating.
(3) Emerging Evidence for the Role of Neurotransmitters. Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 67. the activation of naïve T cells [28, 36-41]. While the signal threshold of antigenic T cell activation is determined by the TCR/pMHC interaction, the magnitude of this threshold, as well as polarization of effector/regulatory phenotype of activated T cells, can be modulated by additional surface and soluble regulatory molecules expressed by DCs at the immunological synapse, as described below.. critical and highly relevant at promoting immunity against pathogens and tumours, avoiding the development of autoimmune damage to self healthy tissues.. 1.3.2. Co-Stimulatory Molecules. Traditionally, it has been described that the function of immune cells, such as T cells and DCs, is regulated by soluble protein mediators known as cytokines. However, an emerging number of studies have shown that immune system cells can be also regulated by neurotransmitters [50]. In this regard, it has been described that several receptors for neurotransmitters classically expressed in the nervous system, such as glutamate (Glu) receptors (GluRs), acetylcholine (ACh) receptors (AChRs), serotonin (5-HT) receptors (5HTRs) and dopamine (DA) receptors (DARs), among others, are also expressed on the surface of immune system cells. Thus, T cells express GluRs [51, 52], DARs [53-56], 5HTRs [57], AChRs [58], noradrenaline/adrenaline (NA/A) receptors [59], -aminobutiric acid (GABA) receptors [60], among others. Furthermore, DCs express GluRs [52], DARs [61], 5-HTRs [62], AChRs [63], and NA/A receptors [64]. Similar to T cells and DCs, neurotransmitter receptors have been found on the surface of a number of other immune system cells, which implicates that these cells could be regulated by molecules from the nervous system. The identification of these receptors on immune system cells suggests that neurotransmitters play a physiological role in the regulation of the immune response and that the dysregulation on the activation of these receptors could be involved on the development of autoimmunity or cancer. Moreover, this fact implicates that different physiological or pathological states of the nervous system could be involved in the regulation of immune response. Furthermore, expression of neurotransmitter receptors on leukocytes and the expression of cytokine receptors on cells from nervous system [65] open new possibilities of bidirectional communication networks between immune system and nervous system. Importantly, a number of recent studies have revealed that some components involved in adaptive and innate immune responses such as DCs, T cells, B cells, macrophages among others, are capable of synthesizing and/or capturing classical neurotransmitters, including ACh, DA, 5-HT and glutamate. Under particular conditions, these cells may release neurotransmitters from vesicular or non-vesicular storages toward extracellular compartment, thus involving autocrine, paracrine, yuxtacrine and, eventually, endocrine communications with different leukocytes [50]. For instance, T cells may release 5-HT [66], NA/A [67], DA [68] and ACh [58]; while DCs may release Glu [69], and 5-HT [66]. This fact not only suggests that neurotransmitters could mediate communication between immune cells, but also that this kind of molecules may be involved in bidirectional cross-talk between immune and nervous system. Due to the key role played by T cells and DCs during adaptive immune responses, here we analyse and discuss several recent studies relative to the contribution of neurotransmitters in the function of these cells. Specifically, we have focussed the discussion on the involvement of DA, Glu, ACh and 5-HT in the function of T cells and DCs and in the interaction between these two important immune cells.. When Ags are captured in a pro-inflammatory environment generated by cytokines or PAMPs, DCs undergo a maturation process consisting on the expression of elevated levels of costimulatory molecules (soluble and membranebound). CD80 and CD86 [42] are two membrane-bound costimulatory molecules that contribute to the immunogenicity of DCs. At the T cell-DC synapse, CD80/CD86 can bind to CD28 on T cells and provide activating signalling. The presence or the absence of these costimulatory surface molecules allow DCs to modulate the nature of T cell responses, promoting either immunity or tolerance respectively. In this regard, it has been described that CD86 promotes costimulation to effector T cells but this molecule regulates negatively activation of Tregs. On the other hand, CD80 induces costimulatory signals for both effector T cells as well as Tregs [42]. In the same direction, it has been described that CD80 display major binding than CD86 for CTLA-4, a surface molecule expressed on activating T cells which, when engaged, trigger inhibitory signals [43, 44]. Importantly, it has been demonstrated that CD80 and CD86 can differentially recruit CTLA-4 and CD28 to the T cell surface modulating T cell activation [45]. These studies together have demonstrated that CD80 is the major ligand involved in mediating CTLA-4 binding and localization, whereas CD86 is the major ligand for CD28 recruitment to the synapse and its stimulation [44, 45]. Regarding the physiological relevance of these preferential interactions, it has recently been demonstrated that whereas CD86/CD28 interaction stimulates effector function of T cells, CD80/CTLA-4 interaction promotes naïve T cell differentiation toward IL-10-producing and TGF--producing inducible-Tregs [46]. The relevance of these findings was underscored by the observation that only CD86-/-, but not of CD80-/- Ag-pulsed DCs were able to improve the development of an autoimmune response in mice [46]. 1.3.3. Cytokines An important system of soluble molecules and their correspondent membrane receptors by which DCs regulate the outcome of immune response is throughout a group of regulatory cytokine secreted by these cells. For instance, IL-12 favours differentiation toward Th1 and impairs Th2 and Th17 differentiation [21, 24]. Whereas IL-6 together with IL-23 facilitate Th17 differentiation [21], IL-6 together IL-4 allow development of Th2-mediated responses [47]. In contrast, by secreting the suppressive cytokine IL-10, tolerogenic DCs promote an suitable environment to induce differentiation of naïve T cells toward inducible Tregs [48, 49]. Consequently, by a coordinate expression of surface and soluble molecules, DCs can either define the nature of an adaptive immune response against a particular antigen or induce tolerance to self constituents. Therefore, DCs are. 2. EMERGING ROLE OF NEUROTRANSMITTERS ON THE REGULATION OF T CELLS AND DCS PHYSIOLOGY.
(4) 68 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 2.1. Modulation of T Cell and DC Function by Dopamine By stimulating different DARs expressed on T cells or DCs, DA from diverse sources may strongly regulate the initiation and development of immune responses. Primary source of DA for patrolling resting naïve or memory T cells and peripheral migrating effector T cells would be plasma DA, which in normal individuals reach levels about 10 pg/ml [55, 70]. Furthermore, dopaminergic innervation of lymph nodes and spleen has been described [71], which suggests the existence of direct DA-mediated regulation by nervous system on activating T cells and resting T cells into secondary lymphoid organs. Depending on the context of the immune response and on the place of inflammation, another important source of DA eventually could be the central nervous system (CNS). In this regard, it has been shown that effector T cells are able to cross the blood brain barrier (BBB) where they would be exposed to a variety of neurotransmitters [72]. Effector T cells can cross the BBB and enter into the CNS due to the high expression of particular cytokines, chemokine receptors and adhesion molecules which interact with surface molecules expressed on the BBB epithelial cells, allowing entrance of these T cells. For instance, 4integrins/VCAM-1 [73] and CXCR3/CXCL-9,-10 or -11 [74], LFA-1/ICAM-1 [75], CCR2/MCP-1 (exclusive for Th2 cells) [75], IL-22/IL-22R and IL-17/IL-17R (exclusive for Th17 cells) [76] mediate interactions of T cell/BBB respectively facilitating entrance of T cells into the CNS. Another source of DA for activating T cells into lymph nodes could be autocrine secretion of DA by T cells [77] and putative paracrine release of this neurotransmitter by DCs during Ag presentation [61] (Fig. (1)). Nevertheless, these latter DA sources consisting on immune cells have not been yet studied in detail. So far, five DA receptors (DARs) have been described (D1-D5), which are hepta-spanning membrane receptors and belong to the superfamily of G protein-coupled receptors [78]. Whereas type I DARs (D1 and D5) are generally coupled to Gs and subsequent stimulation of cAMP production, type II DARs (D2, D3 and D4) are often coupled to Gi promoting inhibition of cAMP synthesis [79]. However, it has been shown that type I and type II DARs also can be coupled to other G proteins, thus triggering signaling pathways different of the increase or decrease of cAMP production respectively [80, 81]. Regarding regulation of TCR-triggered signaling in T cells, PKA (a protein kinase activated by cAMP) as much as cAMP evoke inhibition of ERK [82] and JNK activation [83], activate C-terminal Src kinase (CSK) [84] and block NF-B activation [85, 86] in T cells. All of these intracellular biochemical events induce a marked impairment on T cell activation with inhibition of T cell proliferation and of cytokine production [87]. Thus, by stimulating DARs, DA could regulate T cell function either negatively or positively. In this regard, five DARs (D1-D5) have been described on human T cells, which play diverse function in the regulation of T cell physiology (Fig. (1)). In humans, the D3 receptor promotes stimulating functions in T cells, while D1, D2, D4 and D5 induce inhibitory signals that suppress the T cell function. By coupling to Gi [54], D3-stimulation promotes production of TNF- [53] in CD8+ T cells and also induces. Pacheco et al.. secretion of IFN- and inhibition of IL-10 and IL-4 synthesis in both CD4+ and CD8 + T cells [88]. Furthermore, stimulation via D3 receptor induces a down-regulation of CXCR3 expression on the T cell surface, thereby promoting a homing different to the CNS [74, 88]. In addition, in CD8+ naïve T cells D3-triggered signal stimulates chemotaxis by itself, but also potentiates migration induced by some chemokines such as CCL19, CCL21 and CXCL12 [54]. Moreover, D3 stimulation promotes adhesion to fibronectin via activation of VLA-4 and VLA-5 and adhesion to ICAM-1 through activation of LFA-1 in naïve CD8+ T cells [54]. On the other hand, stimulation of D1/5 receptor, through the rise of intracellular cAMP, impairs proliferation and cytotoxic effector function of CD4+ and CD8 + T cells respectively [55]. D2 stimulation promotes enhanced production of IL-10, a cytokine that regulates negatively the function of effector T cells [53] and it could be involved in the polarization toward inducible Tregs. Stimulation of dopamine D4 receptor induces T cell quiescence by up-regulating Krüppel-like factor-2 (KLF-2) expression through inhibition of ERK1/ERK2 phosphorylation [56] (Fig. (1)). KLF-2 is a critical regulator of quiescence, a state characterized by decreased cell size and metabolic activity of T cells [89]. Activation of D5 receptor has also been related with inhibition of T cell function, including impairment of T cell proliferation, IFN- secretion and expression of matrix metalloproteinase-9 [90]. In fact, a selective decreased expression of D5 in peripheral-bloodmononuclear-cells was found in patients with multiple sclerosis, an autoimmune disorder directed against CNS constituents [90]. DARs have been less extensively studied in mouse T cells, in which type I (D1/D5) and D3 receptors have been identified. In contrast to what has been observed in human T cells, D1/5 as well as D3 receptors are positively coupled to effector T cell function in mouse. For instance, D1/5 receptor inhibits function of Tregs [91], while D3 stimulation, as for human T cells, promotes chemotaxis and cellular adhesion of CD8+ T cells [54] in mouse. In addition, similarly to human T cells, it has been reported that D3stimulation of CD4+ T cells in rats promote increased IFN- production, thus favouring Th1 polarization [88]. With regard to the expression and function of DARs in DCs, it has recently been demonstrated that DCs pre-treated with type I DARs-antagonists are enable to promote amelioration of an autoimmune disease in mice [61]. This effect was due to that treatment with type I DARs-antagonists promotes that DCs acquire the ability to inhibit the generation of Th17-effector phenotype and favour Th1 differentiation in stimulated T cells [61] (Fig. (1)). In contrast, antagonism of type II DARs in DCs increase their capacity to promote the differentiation of Th17 cells, whereas reducing Th1 polarization [61]. Further studies and efforts are necessary to identify mechanisms and specific DARs involved in this antagonistmediated effect on DCs. Participation of DA in the interplay of DCs and T cells is still not clearly demonstrated. Nevertheless, Nakano et al. [61], have suggested that DCs would store DA and, upon interaction with naïve CD4+ T cells, the neurotransmitter is released. Subsequently, DC-released DA, by stimulating type I DARs on T cells, triggers cAMPdependent differentiation of T cells toward Th2 effector cells. An integrative scheme for the role of DA and DARs in the interplay of T cells and DCs as well as in the regulation.
(5) Emerging Evidence for the Role of Neurotransmitters. Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 69. Fig. (1). Role of DA in the interplay of T cell-DC and in the development of T cell response. a, DCs entering to secondary lymphoid tissues may be stimulated by plasma DA, by DA released from themselves or by DA released from neurons. b, Stimulation of type II DARs inhibit bias to Th17 inducer-DCs favouring thus bias to Th1 inducer-DCs. c, In contrast, stimulation of type I DARs, inhibit bias to Th1 and promote bias to Th17 in DCs, d, probably by stimulating production of TGF-, IL-6 and/or IL-23. During Ag presentation by DCs to naïve T cells into secondary lymphoid tissues, stimulation of different DARs expressed on T cells by DA released from T cells or DCs may outcomes in diverse fates for T cells. e, Stimulation of type I DARs on naïve CD4+ T cells promote inhibition of T cell activation toward Th1 and stimulate differentiation to Th2 phenotype. f, Activation of D2 receptor in naïve CD4+ T cells induce production of IL-10 with subsequent differentiation toward Treg. g, Further stimulation of type I DARs on Tregs promote inhibition of ERK1/2 with the subsequent inhibition of suppressor function o these cells. h, Stimulation of D3 receptor expressed in CD4+ naïve T cells induce secretion of IFN-, stimulating Th1 differentiation, and inhibition in the production of IL-10 and IL-4 which impair polarization toward Tregs and Th2 respectively. i, Further activation of D3 receptor expressed on Th1 effector CD4+ T cells induces down-regulation of CXCR3 chemoquine receptor, thus avoiding homing of these cells to CNS. j, Stimulation of dopamine D4 receptor expressed on naïve CD4+ T cells induces T cell quiescence by upregulating Krüppel-like factor-2 (KLF-2) expression through inhibition of ERK1/ERK2 phosphorylation. k, On the other hand, by stimulating D3 receptor expressed on CD8+ naïve T cells, production of IFN- is stimulated and expression of IL-10 and IL-4 is impaired thereby inducing polarization toward IFN--producing and TNF--producing Tc1 effector CD8+ T cells. In addition, stimulation of D3 receptor on naïve CD8+ T cells stimulates chemotaxis by itself or potentiates migration toward CCL19, CCL21 and CXCL12, and also induces adhesion to fibronectin and ICAM-1 by activating integrins VLA-4/5 and LFA-1 respectively. Solid lines represent cellular differentiation, while dotted lines represent secretion, production or effects. Arrow heads mean activation/stimulation/up-regulation/secretion whereas that flat heads represent inhibition/down-regulation. *, only described in humans; **, only described in mice.. of T cell activation and differentiation is represented in Fig. (1). 2.2. Glutamate in the Function of T Cells and DCs The amino-acid glutamate (Glu) may interact with multiple receptor types, divided into two main groups; namely ionotropic Glu receptors (iGluRs), which form ion channels and mediate fast excitatory Glu responses, and metabotropic Glu receptors (mGluRs), which are heptaspanningmembrane-receptors and belong to the superfamily of G protein-coupled receptors [92]. Eight members of the mGluR. family have been identified and classified into three subgroups (I, II, and III) according to their sequence homology, agonist selectivity and signal transduction machinery [93, 94]. Group I contains mGlu1R and mGlu5R subtypes, which are normally coupled to phospholipase C in the CNS. Group II consists of mGlu2R and mGlu3R, and they are negatively coupled to adenylate cyclase in transfected cells. Group III includes mGlu4R, mGlu6R, mGlu7R and mGlu8R, which are again negatively coupled to adenylate cyclase. On the other hand, three major groups of iGluRs are recognized [95], based on their sequence homology and selective activa-.
(6) 70 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. tion by the agonists N-methyl-D-aspartate (NMDA), kainate (KA) or -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Glu-mediated signaling has not only been described in the CNS [92], but also in the immune system [52]. Because human T cells express several Glu receptors and also differential expression of these receptors is triggered by T cell activation [51, 69], it is thought that Glu is an important regulator of T cell function. Patrolling resting T cells encounter plasma Glu, whose concentration fluctuates in the range 10-60 μM [96-98] in physiological conditions. After thymic maturation, resting T cells express group I mGluRs (mGlu5R), group II mGluRs (mGlu2/3R), the group III mGluR member mGlu8R and ionotropic receptors NMDA, AMPA and KA [52]. By stimulating the adenylate cyclasecoupled mGlu5R [51], plasma Glu may keep elevated intracellular cAMP levels with subsequent PKA activation which, as commented above, induce a marked impairment on T cell activation with inhibition of T cell proliferation and of cytokine production [87]. It is noteworthy that mGlu5R in cells of the nervous system is usually coupled to phospholipase C and not to adenylate cyclase. This constitutes a distinctive feature of signalling via mGlu5R in T lymphocytes [51]. Regarding the function of the AMPA receptor iGlu3R in T cells, its stimulation facilitates the chemotactic migration toward a CXCL12 gradient and promotes integrin-mediated adhesion of patrolling resting T cells to laminin and fibronectin [99]. On the other hand, NMDA-mediated signaling in T cells promotes also adhesion to fibronectin [100] and inhibits IL-2-mediated enhancement of IFN- production as well [101]. In addition, the amplitude of calcium influx during the initiation of T cell activation may be regulated by iGluRs via their cation channel activity [102], and by group II mGluRs, which modulate potassium currents through Kv1.3 channels [103]. Nevertheless, because both iGluRsmediated and goup II mGluRs-mediated regulation of calcium/potassium currents in T cell activation are positively modulated at low Glu concentrations but negatively modulated at high Glu levels [102-104], it has been difficult to understand the physiological significance of these receptors on T cell activation. Thereby, further experimental work is necessary to provide an integrated view of the role of these Glu receptors in the T cell physiology. Recently, we have demonstrated that undergoing maturation and during Ag presentation, DCs release Glu via the cystine/Glu antiport, Xc- system [69]. In agreement with these findings, it has been reported that after freund’s adjuvant injection, Glu levels are increased in lymph nodes [105]. From these results it can be surmised that DC-released Glu acts early during T cell-DC interaction via mGlu5R, which is positively coupled to the adenylate cyclase [51], thereby impairing IL-6 production and, consequently, T cell proliferation [69]. Therefore, it is possible that this mGlu5Rmediated mechanism may contribute to avoid T cell activation when non-specific Ags are presented by DCs. Thus, mGlu5R stimulation could lead to inhibiting activation of non-specific T cells in the lymph nodes (Fig. (2)). NMDAmediated signals are also involved in avoiding activation/differentiation of naïve T cells toward Th1 effector phenotype [101]. In addition, stimulation of iGlu3R by DCreleased Glu could contribute to keep migratory activity in. Pacheco et al.. resting T cells [99]. In contrast, when DCs present the cognate-Ag to T cells, the latter are engaged and undergo an activation process. Under these conditions the mGlu1R expression is induced on activated T cells, which so far, has been the only T cell activation-inducible Glu receptor described [51, 69]. Subsequently, DC-released Glu acts on the induced mGlu1R, which is coupled to the ERK-pathway [51]. In this way, Glu causes the attenuation of the inhibitory mGlu5R-triggered effects as well as the enhancement of Th1 (IL-2 and IFN-) and pro-inflammatory (IL-6 and TNF-) cytokine secretion inducing potentiation of T cell activation [69]. Moreover, it has been demonstrated that stimulation of mGlu1R inhibits activation-induced cell death in effector T cells [106], thereby prolonging the duration of effector T cell response. The mGlu1R-mediated stimulatory effect in combination with the mGlu5R-mediated inhibitory effect could constitute a fine tuning regulatory mechanism by which little differences in the intensity of TCR-triggered stimulus would allow different T cell-fate decisions in response to Agspecific and non-specific T cells (Fig. (2)). In addition to plasma and APCs, the CNS is also an important source of Glu for T cells [72]. In this regard, it has been proposed that, by stimulating mGlu1R expressed on effector Th1 cells, Glu would play a key role on minimizing the Glu-induced neuronal damage during protective autoimmunity [52]. Regarding the involvement of Glu receptors during the migration of effector T cells, Ganor et al. [107] have described that after T cell activation, T cells begin to release granzyme B which in turn, degrades iGlu3R. These results suggest that degradation of iGlu3R, which stimulates adhesion to fibronectin and laminin and also promotes strong chemotactic migration toward CXCL12 [99], could constitute a mechanism by which effector CD8+ T cells as well as CD4+ T cells [108, 109] may be retained in the site of infection to mediate pathogen/tumour elimination (Fig. (2)). In contrast to human T cells, expression and function of Glu receptors have been poorly studied in mice. Boldyrev et al. [110] have reported that in contrast to data available for human T cells, rodent lymphocytes express group III mGluRs, but neither group I nor group II mGluRs are present in these cells. In addition, the same authors have demonstrated that rodent lymphocytes express NMDA receptors, which mediate increases of intracellular calcium and reactive oxygen species. Finally, addressing the expression of Glu receptors on DCs, mGluRs have been found in rat thymic DC [111]. Whereas cortical DC express mGlu2/3R and mGlu4R weakly, medullar DC show moderate mGlu2/3R and mGlu4R and strong mGlu5R expression [111]. However, we have recently demonstrated that neither mGlu1R nor mGlu5R are expressed on human monocyte-derived DC surface [69]. This discrepancy in the expression of mGlu5R in DC may be due to a different pattern of expression of Glu receptors in DCs from different species and in DCs from different locations. 2.3. Regulation of the T Cell Mediated Immunity by Acetylcholine The neurotransmitter acetylcholine (ACh) may promote diverse effects on target cells by stimulating ACh receptors.
(7) Emerging Evidence for the Role of Neurotransmitters. Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 71. Fig. (2). Involvement of glutamate and glutamate receptors in the function of human T cells during Ag presentation and effector stage. a, During Ag presentation into secondary lymphoid tissues, DCs undergoing maturation begin to release high levels of Glu through the cystine/Glu antiport (Xc-). b, Glu released by DCs stimulates the mGlu5R expressed on resting naïve CD4+ and CD8+ T cells, which promotes increase of intracellular levels of cAMP. c, rise of cAMP evokes inhibition of ERKs and JNKs activation, activates C-terminal Src kinase and blocks NF-B activation. All of these intracellular biochemical events induce a marked impairment on T cell activation. d, stimulation of NMDA receptors involves inhibition of IFN- production, thereby avoiding subsequent differentiation toward Th1 or Tc1 cells from naïve CD4+ of CD8+ T cells respectively. e, activation of the AMPA receptor iGlu3R on naïve T cells facilitates adhesion to fibronectin or laminin and also potentiates chemotactic migration toward CXCL12. Once activated, effector T cells begin to express mGlu1R on the cell surface. f, stimulation of mGlu1R by Glu triggers activating signals that, by bypassing mGlu5R-derived signaling, evokes ERK1/2 activation. g, subsequently, ERKs-mediated signals induces strong potentiation on the production/secretion of Th1/Tc1 cytokines IFN- and IL-2 and also TNF-, IL-6 and IL-10. Moreover, h, mGlu1R-triggered signaling promotes inhibition of activation-induced-cell-death (AICD). i, cytotoxic CD4+ or CD8+ T cells, during effector response release granzyme B (GB), a serine protease that promotes apoptosis on infected/tumour cells. j, released GB mediates subsequently the cleavage of iGlu3R, eliminating thus the biological activity of this receptor. Lack of iGlu3R avoids further Glu-induced adhesion and Glu-facilitated migration outside of the infected/tumour tissues. To clarify the scheme, some Glu receptors with still not well established role on the function of T cells or DCs have been omitted. Solid lines represent cellular differentiation, while dotted lines represent secretion, production or effects. Arrow heads mean activation/stimulation/upregulation/secretion whereas that flat heads represent inhibition/down-regulation.. (AChRs) expressed on the surface of those cells. AChRs described are classified in two main groups; namely nicotinic AChRs (nAChRs), which form ion channels and mediate fast excitatory ACh responses, and muscarinic AChRs (mAChRs), which are heptaspanning-membrane-receptors and belong to the superfamily of G protein-coupled receptors [112, 113]. Five mAChRs subtypes have been cloned (M1M5) and they are generally divided into two distinct classes based on signal transduction. Whereas M1, M3 and M5 mAChRs subtypes usually couple via Gq/11 proteins to activate phospholipase C and subsequent mobilization of calcium, M2 and M4 mAChRs are predominantly coupled through Gi/o proteins to inhibit adenylate cyclase inducing thus decrease on intracellular levels of cAMP [112]. On the other hand, nAChRs are composed by five homologous subunits organized around a central pore. Up to date, 17 types of subunits have been cloned including 1-10, which. carry the main parts of ligand-binding-sites, 1-4, , , and subunits [113]. The precise composition of hetero- or homo- pentamers determinates specific pharmacological properties of these receptors [113]. Glu, DA, and 5-HT among others, constitute a group of physicochemically and enzymatically stable molecules, which may act on cells relatively far from where these neurotransmitters were originally released (volume transmission) [50]. Thus, substantial amounts of these neurotransmitters can be detected in extracellular fluids including plasma and their role as neurotransmitters is terminated mainly by reuptake into nerve terminals and tissues. In contrast, ACh belongs to the group of labile compounds which, when released, achieve effective concentrations to act over target cells by just less than several milliseconds due to its rapid degradation by cholinesterases that are abundant in tissues.
(8) 72 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. and plasma [50]. Thereby, very low ACh levels are detected in plasma (pg/ml range, [114]) and it seems likely that ACh primarily acts over immune system by wiring transmission between closely interactions leukocyte:leukocyte or neuron:leukocyte. Regarding ACh sources for T cells, it is likely that primary source for these cells are themselves when they undergo cellular activation [115, 116]. ACh released from activated T cells may lead to high local concentrations of ACh, and autocrine/paracrine signalling via ACh receptors expressed on these cells. Importantly, lymph nodes have an additional source of ACh from autonomic nerve terminals [71] which may also contribute to cholinergic signalling in T cells. Thus, it is likely that this ACh-mediated pathway constitutes a communication between nervous system activity and immune response. In addition to T cells and autonomic nervous that innervate lymph nodes, the CNS is also a source of ACh for effector T cells that cross the BBB and enter into the brain [72]. Another source of ACh for T cells, which may be an important contribution during first stage of T cell activation, are DCs. In this regard, it has been described that when undergoing maturation, DCs begin to express cholineacetyl-transferase (ChAT) with the consequent production of ACh [63]. These findings suggest that ACh would be released during Ag presentation to T cells (Fig. (3)). For many years, ACh has been known as a neurotransmitter mediating transmission in the central and peripheral nervous system, however, it is now evident that all of components of cholinergic system are expressed also in T cells [58]. First, in 1993 ChAT activity was found inside lymphocytes [115] and in 1998 it was corroborated that this activity promotes synthesis and storage of ACh in T cells [114]. Not only ACh and ChAT activity have been described in T cells, but also nAChRs, mAChRs, cholinesterase activity and choline transporters have been found on the surface of these cells [58]. Regarding AChRs expression on T cells, it has been described that M3 is the most strongly expressed mAChRs followed by M5 and M4, whereas that M1 and M2 expression is substantially variable among individuals [58, 117]. Expression of nAChRs on T cells is mainly constituted by receptors bearing subunits 2, 5 and 7 as the component of these pentameric receptors [58, 118]. Muscarinic stimulation on T cells triggers intracellular calcium oscillations followed by c-fos up-regulation [119], which consequently promotes potentiation of T cell activation with strong IL-2 production [120]. Fujii and Kawashima have concluded that this mAChRs-mediated potentiation of T cell activation is mediated by the M3 subtype [121]. Importantly, M3 as well as M5 mAChRs are up-regulated after T cell activation [122]. Furthermore, Zimring et al. [123] have demonstrated that autocrine stimulation of the M1 subtype of mAChRs is not required for initial T cell activation, but further for differentiation from naïve CD8 + T cells toward effector cytotoxic CD8+ T cells in mice. In addition, an impairment of specific anti-ovalbumin IgG1 antibodies and IL6 production in vivo have been shown in ovalbuminimmunized M1/M5 double-knockout mice when compared with wild-type control animals [124]. Because IgG1 constitute a prototypic Ig isotype of Th2 responses [125], these results suggest that stimulation of M1 and/or M5 mAChRs expressed on CD4+ T cells would be responsible to potentiates IL-6 production by Th2 cells (Fig. (3)) to further pro-. Pacheco et al.. mote switch of isotype from IgM to IgG1 in B cells [126]. Regarding function of nAChRs on T cells, it has been demonstrated that nicotine, mainly through 7-bearing nAChRs, triggers calcium influx into these cells [127]. Addressing the further effect of nicotine in the function of lymphocytes and its involvement on the immune response, it has been reported that activation of nicotinic receptors on concanavalin Astimulated splenocytes promotes a potentiation of IFN- production and inhibition of IL-10 release [128]. These findings suggest that nAChRs-mediated stimulation promotes Th1 differentiation while impairs Tregs generation. According to this notion, increased levels of anti-ovalbumin specific IgG1, an isotype of the Th2 response, were found in serum from ovalbumin-immunized 7-KO mice [129]. Nevertheless, in the same in vivo study, the authors found an generalized increase on serum cytokines, including IFN-, TNF- and IL-6 from ovalbumin-immunized 7-KO mice [129], which suggest that other nAChRs different from 7-bearing nAChRs are also responsible for polarization of the immune response toward Th1 effector phenotype (Fig. (3)). Addressing the role of ACh in DCs, expression of nicotinic as well as muscarinic AChRs have been recently described in DCs [63]. However consequences in the DC physiology upon stimulation of these AChRs have been poorly studied. In this regard, the only study available has recently demonstrated that by targeting 7-bearing nAChRs on DCs ex-vivo, these cells produce increased IL-12 secretion, which in turn, induces enhanced stimulation of cytotoxic CD8+ T cells with a consequent improvement of anti-tumour response in vivo [130]. These results suggest that stimulation of 7-bearing nAChRs on DCs promotes a pro-Th1 phenotype on these cells which stimulates polarization of naïve T cells toward Th1 (Fig. (3)). 2.4. Role of Serotonin on the Function of T Cells and DCs So far, fourteen serotonin receptors (5-HTRs) have been described, 13 of them belonging to the G-protein coupled receptors family and one ligand-gated ion channel. According to their sequence homology and signal transduction machinery, G-protein coupled 5-HTRs are divided in three groups: 5-HT1A, 5-HT2, 5-HT7-like receptors. The 5-HT1A group comprises subtypes 1A, 1B, 1D, 1E, 1F, 5A and 5B, which are negatively coupled to adenylate cyclase by Gi/o protein. The second group, 5-HT2, comprises receptors 2A, 2B and 2C, which are coupled to phospholipase C through Gq/11 protein, whereas that the 5-HT7 like group, (subtypes 4, 6 and 7) usually are positively coupled to cAMP production via Gs protein. On the other hand, 5-HT3 is a cation-selective ion channel comprised by five pseudosymmetrical subunits that surround a central ion channel, a structure very similar to nicotinc AChRs [131]. The main source of serotonin for patrolling resting T cells is plasma serotonin which in healthy individuals fluctuates among 60 nM [132]. Importantly, serotonin levels in plasma may be significantly increased by platelet-derived serotonin which is highly released under platelet activation [133]. Other important sources of serotonin into secondary lymphoid organs are DCs and T cells itself. When TLRs expressed on DCs are stimulated by PAMPs, these cells increase expression of serotonin transporters (SERTs) which mediate uptake and storage of environmental extracellular serotonin into LAMP-1+ secretory vesicles. Subsequently,.
(9) Emerging Evidence for the Role of Neurotransmitters. Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 73. Fig. (3). Role of ACh and AChRs on the function of DC and T cells during Ag presentation and further differentiation. a, Under TLRs stimulation by PAMPs, DCs undergo maturation and begin to express ChAT which mediates synthesis of ACh to be further released during Ag presentation to T cells into secondary lymphoid tissues. b, autonomic cholinergic terminals also can release ACh into lymph nodes contributing thus to increase levels of local ACh able to stimulate AChRs expressed on T cells and DCs. c, stimulation of 7-bearing nAChR on DCs induces production and release of IL-12, a pro-Th1/Tc1 cytokine. d, when cognate Ag is presented by mature DCs to naïve T cells, these latter become activated and begin to release ACh, which further may stimulate AChRs on T cells and DCs in an autocrine/paracrine manner. e, upon activation process, T cells produce and release IL-2, the main growth factor for T cells, which may be inhibited by cAMPcoupled stimulation of M2/4 mAChRs. f, in contrast, stimulation of the phospholipase C-coupled M3 muscarinic AChR on T cells potentiates IL-2 production promoting strong T cell activation. g, later during activation of CD8+ T cells, stimulation of M1 mAChR is required to promote proper differentiation to cytotoxic effector CD8+ T cells. h, IL-12 released by DCs induces polarization from naïve CD8+ T cells toward Tc1 effector phenotype. On the other hand, i, stimulation of 7-bearing nAChRs on naïve CD4+ T cells potentiates production of IFN- whereas attenuates secretion of IL-10 which together favours polarization toward Th1 effector phenotype. j, DC-derived IL-12 induces additionally polarization toward Th1 phenotype on CD4+ T cells. k, the stimulation of nAChRs different to 7-bearing receptors, probably 2- and/or 5-bearing nicotinic receptors, allow Th2 polarization. l, further function of Th1/Tc1 effector cells inhibits tumour growth. m, activation of muscarinic M1/5 receptors on Th2 cells potentiates IL-6 production, which in turn facilitates switch of Ig isotype toward IgG1 on B cells. To clarify the scheme, some AChRs with still not well established role on the function of T cells or DCs have been omitted. Solid lines represent cellular differentiation, while dotted lines represent secretion, production or effects. Arrow heads mean activation/stimulation/up-regulation/secretion whereas that flat heads represent inhibition/down-regulation. *, only described in humans; **, only described in rodents.. when mature DCs present Ags to T cells into lymph nodes, DCs release these serotonin-containing vesicles on T cells [66]. Furthermore, IFN-, a cytokine released mainly by plasmacytoid DCs in response to viral-derived PAMPs, induces increased expression of SERTs on T cells with the subsequent uptake of serotonin by these cells [134]. When T cells enter into the activation process, they also begin to release serotonin [66], which may act autocrinely or paracrinely over themselves. In addition to T cells, DCs and. plasma, the CNS is also a source of serotonin for effector T cells that cross the BBB and enter into the brain [72]. Several 5-HTRs have been described in T cells including subtypes 1A, 1B, 2A, 2B, 2C, 3 and 7. Early studies addressing the role of serotonin on the T cell function demonstrated that depletion of intracellular storage of serotonin from T cells impairs T cell activation and proliferation in response to polyclonal stimuli. Moreover, proliferative and activation responses were recovered by addition of exogenous sero-.
(10) 74 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. tonin, suggesting that this molecule play an important regulatory role in the activation of T cells [135]. Actually, it has been demonstrated that, indeed, serotonin is required for proper T cell activation early by stimulating 5-HT7 [57] and 5-HT3 [136, 137] expressed on naïve T cells, and later by stimulating 5-HT1B and 5-HT2C expressed on activating T cells [138]. In this regard, early stimulation of 5-HT7 promotes enhanced phosphorylation of ERK1/2 and activation of NF-B facilitating thus strong T cell activation [57]. In addition, stimulation of the ion channel 5-HT3 on a human CD4+ leukemia T cell line allow influx of Na+ [136], which in turn induces activation of protein kinase C (PKC) and phospholipase D (PLD), favouring T cell proliferation and progression from S-phase to G2/M-phase of the cell cycle [137]. The 5-HT1A receptor has been involved in the polarization of naïve CD4+ T cells toward Th1 effector phenotype [139] and further potentiation of cytotoxic function of NK cells [140]. Also during T cell activation, stimulation of 5HT1B expressed on naïve T cells [57], triggers decrease of intracellular cAMP, thereby modulating positively the T cell activation [66]. However, because high expression of 5-HT1B is induced after initial stages of T cell activation [57], it seems that serotonin-mediated effects through of this receptor are relevant in advanced stages of the process of T cell activation. Similarly, 5-HT2C has been involved in potentiating T cell activation and proliferation during later stages of this process [135, 138]. These 5-HT2 has been also involved in serotonin-mediated inflammatory process by promoting secretion of IL-16 from effector CD8 + T cells, a chemokine that, in turn, attract to CD4+ T cells [141]. This serotoninmediated mechanism could be relevant in recruiting CD4+ T cells to the place of inflammation/infection (Fig. (4)). Although serotonin plays a stimulatory role on the regulation of T cell function, it has been described that this molecule displays tolerogenic role when stimulates 5-HTRs on monocytes/DCs [62, 142]. In this regard, it has been described that by stimulating 5-HT1/7 receptors on differentiating monocytes, these cells become DCs with reduced expression of costimulatory molecules and they produce high levels of IL10 and low levels of IL-12 [62]. Idzko et al. [142] have described that whereas immature DCs express 5-HT1- and 5HT2-like receptors coupled to calcium mobilization, mature DCs express 5-HT7-like receptors which couple to intracellular cAMP rise. Of importance, this study has further shown that stimulation of 5-HT7-like receptors on mature DCs potentiates production of pro-inflammatory cytokines, IL-1 and IL-8 but it decrease release of IL-12 and TNF- [142] (Fig. (4)). Thus, collectively these findings suggest that serotonin, would avoid the development of a Th1-polarized response when acts over monocytes/DCs previously to the encounter with T cells. However, when stimulates directly T cells, serotonin would be a pro-Th1 agent (Fig. (4)). 3. ALTERATIONS IN THE NEUROTRANSMITTERMEDIATED T CELL REGULATION AND THEIR INVOLVEMENT ON THE DEVELOPMENT OF DISEASES The presence of neurotransmitter-mediated regulatory systems involved in the modulation of immune responses suggests that dysregulation of components of these systems could be involved in the triggering, development or progres-. Pacheco et al.. sion of immune-related or neuroimmune-related diseases. According to this notion, imbalance on plasma levels of some neurotransmitters and dysregulation on the expression of neurotransmitter receptors on T cells have been described. 3.1. Involvement of Alterated Plasma Levels of Neurotransmitters in Immune- and Neuroimmune-Related Diseases In general, there is a trend in which neurotransmitters with inhibitory function on T cells, for instance Glu, are increased on immunodeficiencies and cancer but decreased in autoimmune disorders (Table 1), exacerbating thus the immune response. Thereby, this trend could constitute an important factor in the pathophysiology of these diseases which should be taken in account for the treatment and/or diagnosis. Thus, mGlu5R stimulation by plasma Glu would promote an increased threshold for T cell activation, which could be exacerbated in some pathologies (Table 1). Furthermore, not only plasma Glu may activate Glu receptors expressed in patrolling resting T cells, but also homocysteine and its metabolic derivatives may stimulate either mGluRs or iGluRs [143, 144]. Normal plasma homocysteine levels are in the range 5-15 μM, but they may increase up to >100 μM in pathophysiological conditions such as in neurodegenerative or cardiovascular diseases [145]. Similar studies have shown increased plasma levels of DA in cancer patients and under chronic or acute forms of stress [55, 70, 146]. The exposition of T cells to such elevated DA concentrations in vitro outcomes in the inhibition of T cell proliferation and cytokine secretion [147]. However, there are exceptions to this trend such as elevated plasma Glu in multiple sclerosis, which could have relation with the high levels of extracellular Glu found in the CNS which displays stimulatory effect on activated T cells during this kind of autoimmunity [52]. In the same direction, plasma levels of neurotransmitters that possess stimulatory role on T cell function, such as serotonin, are elevated on autoimmunity (Table 1). Nonetheless, there are exceptions to this trend such as elevated plasma serotonin in cancer. There are evidences that these strong elevation of plasma serotonin in patients with cancer is due to secretion of serotonin by tumours themselves [148]. Indeed, it has been described that after surgery to remove tumours, plasma serotonin decreases dramatically [148]. It is likely that this release of serotonin constitutes a mechanism by which tumours may evade immune response by affecting both the differentiation from monocytes to dendritic cells and the phenotype of immature DCs taking up tumourderived Ags. In this regard, differentiation toward DCs is affected by high levels of serotonin which outcomes in the generation of tolerogenic dendritic cells [62]. Furthermore, differentiated DCs capturing tumour Ags may be induced by serotonin to release high levels of IL-10 but low IL-12 [62, 142] which in turn would impairs T cell response against tumours. Regarding the imbalanced levels of different plasma neurotransmitters upon diverse neurologic disorders (Table 1), it may be complex to establish the cause of the imbalance, nevertheless, the effect of this imbalance on the T cells function may sometimes outcomes quite predictable. For instance, the pathophysiological state of stress promotes in-.
(11) Emerging Evidence for the Role of Neurotransmitters. Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 75. Fig. (4). Role of serotonin in the interplay of T cell-DC and in the development of T cell response. a, in the presence of serotonin (5-HT), by stimulating 5-HT1/7 receptors, monocytes differentiate to tolerogenic DCs, which express low density of surface costimulatory molecules and strongly release IL-10 but nor IL-12. b, in contrast, in the absence of 5-HT, monocytes may differentiate toward immunogenic DCs. c, by stimulation of 5-HT4/7 receptors on mature DCs, serotonin triggers intracellular cAMP elevation with consequent inhibition of IL-12 production and potentiation on the release of IL-8 and IL-1. d, under stimulation of TLRs by PAMPs, expression of SERTs is up-regulated in DCs. Subsequently, SERTs promote uptake and storage of 5-HT into LAMP-1+ secretory vesicles. e, when presenting Ags to cognate T cells, DCs release 5-HT-containing vesicles over T cells. f, Stimulation of 5-HT7 on naïve CD4+/CD8+ T cells triggers activation of ERKs and NK-B whereas stimulation of 5-HT3 induces Na+/Ca2+ influx triggering activation of PKC and PLD. Both 5-HT7-triggered as well as 5-HT3-induced intracellular effects enhance T cell activation and proliferation. g, activating T cells release 5-HT and later during the activation process, CD4+/CD8+ T cells begin to express 5-HT1 and 5-HT2. Stimulation of 5-HT1 and 5-HT2 on activating T cells is required to complete activation process. h, furthermore, stimulation of 5-HT1A on CD4+ T cells induces polarization toward Th1 phenotype. i, importantly, stimulation of 5HT2 on effector CD8+ T cells induces production and release of IL-16, a chemokine that recruit CD4+ T cells, j. Solid lines represent cellular differentiation, while dotted thin lines represent secretion, production or effects. Arrow heads mean activation/stimulation/upregulation/secretion whereas that flat heads represent inhibition/down-regulation. Wide dotted line represents chemotactic effect toward the arrow head indicates. *, only described in humans; **, only described in mice.. creased plasma Glu and DA, which outcomes in the inhibition of T cell function and therefore immunedepression. These findings collectively suggest that selective stimulation of determined neurotransmitter receptors on T cells, which may be carried out by administration of selective agonist/antagonists, could improve T cell response in some neurological and immune-related pathologies. According to the activating effect that serotonin play on the function of T cells, beneficial effects of serotonin have been described for pathologies involving dysfunction of immune response such as AIDS [149] and malignancies [150]. Importantly, serotonin not only modulates function of T. cells, but also it can regulate physiology of other immune cells relevant in the response against tumours or pathogens. For instance by stimulating the 5-HT1A receptor, cytotoxic function of NK cells is increased by serotonin [140], which could be taken in account for the design of immune-based therapies, similarly to the beneficial serotonin-mediated therapeutic effect described recently for T cell mediated antitumour immunity [150]. On the other hand, according to the regulatory role that serotonin plays by inducing a tolerogenic phenotype on DCs [62], DC-based immunotherapies geared toward improve autoimmunity or to avoid graft rejection could take advantage of these findings to generate tolero-.
(12) 76 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. Table 1.. Pacheco et al.. Dysregulation of Plasma Neurotransmitters in Some Immune-Related Pathologies. Classification. Pathology. Neurotransmitter. Increase (In-fold)(a). Reference. Amyotrophic lateral sclerosis. Glu. 4.8 ± 3.4. [156]. Dementia of the Alzheimer type. Glu. 0.66 ± 0.29. [157]. Epilepsy. Glu. 2.7 ± 1.3. [158]. Glu. 1.4 ± 0.6. [159]. 5-HT. 0.65. [160]. HIV-associate dementia. Glu. 5.9 ± 0.9. [161]. Parkinson's disease. Glu. 2.1 ± 0.3. [162]. DA. 1.85. [146]. Glu. 1.23 ± 0.04. [163]. Diabetes mellitus type I. Glu. 0.82 ± 0.06. [164]. Multiple sclerosis. Glu. 1.49 ± 0.1. [164]. Systemic Lupus Erythematosus. 5-HT. 1.89. [165]. Breast cancer. Glu. 2.0 - 3.0. [166]. Colorectal carcinoma. Glu. 1.7 - 3.1. [166]. Lung cancer. DA. 4.76. [70]. Intestinal cancer. 5-HT. 11.2 ± 3.6. [148]. Hepatoma. 5-HT. 7.3 ± 2.4. [148]. AIDS. Glu. 2.0 - 2.6. [166]. Headache (cerebral infarction) Neurologic disorders. Stress. Autoimmunity. Malignancies. Immunodeficiency. (a) Increase of plasma neurotransmitter levels are expressed as the ratio of average of neurotransmitter concentration in plasma from patients versus average of neurotransmitter concentration in plasma from healthy donors.. genic DCs ex-vivo. Intriguingly, despite the tolerogenic effect that serotonin promotes on the phenotype of DCs [62], these studies show a beneficial role of serotonin in the T cell mediated response against tumours in vivo [150]. Because serotonin displays contrary roles on T cells and DCs, these discrepancies in the effect of serotonin on the immune response may be due to the temporality and targeted cells for agonist/antagonist administration. 3.2. Alterated Expression of Neurotransmitter Receptors on T Cells in Immune- and Neuroimmune-Related Disorders Not only imbalance of plasma levels of neurotransmitters may affect T cell function, but also the dysregulation of neurotransmitter receptors expressed on T cells. Accordingly, abnormal expression of these receptors on T cells has been described in several immune-related and neuroimmunerelated pathologies (Table 2). In this regard, elevated expression of neurotransmitter receptors with stimulatory role in the T cell function and decreased level of inhibitory receptors have been described in T cells from patients with autoimmunity. In contrast, decreased expression of stimulatory receptors has been described on T cells from individuals with immunodepressive states, such as found in smokers (Table 2). Accordingly, after chronic exposition to nicotine, a consequent down-regulation of 7- and 6- bearing nAChRs at. one week and decreased expression of 2- and 5- subunits at 8 weeks have been reported [127]. Consistent with these findings, down-regulation of 5 and 7 subunits have been found in lymphocytes from smokers when compared with non-smokers individuals [127]. Thereby, because nicotinic receptors play a stimulatory role on the T cell response, this nAChRs down-regulation found on T cells from smokers could explain, at least in part, the immunosuppression observed in smokers individuals. Importantly, it has been demonstrated that antagonism of nAChRs inhibits smokemediated tumour growth [151], probably by avoiding nAChRs downregulation on T cells after chronic exposure to smoke. Therefore, imbalanced neurotransmitter receptors expression on T cells seems to be also an important factor that must be considered for the design of therapies for immune-related diseases. Neurotransmitter receptors dysregulation on T cells has been also described in several neurological disorders (Table 2), which could have serious consequences in the function of the immune system. Indeed, some studies have suggested that the RNA levels of specific DARs subtypes expressed on T cells could be used as peripheral markers for clinical diagnosis of these neurological and immune-related diseases. More important, all of these studies point to that functional dialogue between DA and T cells might be either up- or.
(13) Emerging Evidence for the Role of Neurotransmitters. Table 2.. Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. 77. Imbalanced Expression of Neurotransmitter Receptors in Human T Cells in Some Neurological or Immune-Related Pathologies. Disease Classification. Neurological/psychiatrical. Pathology. Receptors (a). Cells (b). Reference. Alzheimer's disease. Type II DARs. PBMC. [167]. Amyotrophic Lateral Sclerosis. mGlu2R. PBMC. [168]. Migraine. D3, D4, D5. PBMC. [169, 170]. Parkinson's disease. D3. PBMC. [171]. D3. T cells. [172-174]. D4. CD4+ T cells. [172]. nAChR-7. PBMC. [175]. D5. T cells. [90]. iGlu3R (AMPA). PBMC. [104]. nAChR-5, nAChR-7. PBMC. [127]. Schizofrenia. Autoimmunity Immunodeficiency. Multiple Sclerosis Smoke-induced immunosuppresion. (a) arrows indicate increased or decreased expression of receptors respect to the control conditions from healthy individuals. (b) PBMC: peripheral blood mononuclear cells.. down-regulated in these diseases, which must play a key element in the pathological scenario. According to this idea, it has been demonstrated that administration of an D2agonist to mice during encephalomyelitis autoimmune experimental (EAE), an autoimmunity model in mice similar to multiple sclerosis in humans, outcomes beneficial in the clinical course of development of this disease [152]. Another work supporting this notion have recently been performed by Nakano et al. [61] where these authors described that DCs pre-treated with type I DARs-antagonists are enable to promote amelioration of EAE by impairing differentiation of naïve T cells toward Th17 cells, the pathogenic effector phenotype in this pathology [61]. In fact, during last years, DA has been highly involved in the regulation of the phenotype of the effector T cell response (Fig. (1)). Indeed, it has been demonstrated that the ratio IFN/IL-4 in plasma is significantly higher in medication-naïve (first onset) or without medication schizophrenic patients than in healthy controls, and that the increased levels of IFN/IL-4 were attenuated by effective neuroleptic treatment [153, 154], indicating how dopaminergic regulation may influence Th1/Th2 polarization. Another factor involved in the neurotransmitter-mediated regulation of T cell function is the genetic. In this regard, some polymorphisms of neurotransmitter receptors have been associated with immune-related diseases, indicating thus the important role of such receptors in the development of those diseases. For instance, a polymorphism of the D2 receptor, an important DARs involved in the differentiation of CD4+ T cells toward Tregs (Fig. (1)), has been related with the generation of colorectal cancer [155]. 4. CONCLUDING REMARKS AND FUTURE PERSPECTIVES The evidence points to the emergence of neurotransmitters as key molecules in the initiation and regulation of T cell. responses, thereby they have important roles on the development and progression of immune-related or neuroimmunerelated diseases. Several studies have shown expression of diverse neurotransmitter receptor subtypes on DCs and T cells or T cell lines from different sources and differentiation stages. However, some ambiguities with respect to the specific cellular pool or the differentiation stage in which some receptors are expressed remains pending to be clarified. Therefore, further efforts are still necessary to identify clearly the pool of neurotransmitter receptors expressed by subpopulations of T cells and DCs under each defined stage during cellular differentiation. Similarly, identification of sources of these molecules for T cells is an active research field. Neurotransmitters have not only involved in nervous-driven regulation of immunity, but also in leukocyte-driven regulation of immunity. In this regard, DCs as well as T cells and other immune cells have been described as sources of neurotransmitters, which are released under defined conditions. However target cells and physiological roles for these leukocyte-derived neurotransmitters remains, in several cases, not well defined. Therefore, further studies are still necessary to determine physiological relevance of immune-driven release of neurotransmitters, their roles, both individual and synergistic, and their mechanism of action. In this direction, physiological studies about the role of leukocyte-derived neurotransmitters over the nervous system should be approached as well. These studies would allow elucidate direct bidirectional mechanisms of neuro-immune communication, which could give a better understanding of physiological mechanisms or those operating in pathologies involving leukocyte infiltration into the brain such as multiple sclerosis. Further insight of neurotransmitter-mediated regulation of immune function is critical to understanding their role in imbalanced immune response, including autoimmunity, im-.
(14) 78 Central Nervous System Agents in Medicinal Chemistry, 2010, Vol. 10, No. 1. munodeficiency and tumour growth. The relevant involvement of neurotransmitter-mediated regulation of immune response is evidenced by the dysregulation of neurotransmitter receptors expressed on T cells and by alteration of plasma levels of these molecules, both conditions found as part of the pathophysiological scenario in several immune-related and neurological disorders. In this regard, dysregulation of neurotransmitter receptors expression and plasma levels of these molecules follow a general trend geared toward exacerbate imbalance of immune response. Accordingly, upregulation of stimulatory neurotransmitter receptors and down-modulation of inhibitory receptors are found in T cells during autoimmunity. In contrast, downregulated activating receptors and increased levels of inhibitory receptors are found on T cells from patients with immunodeficiency or cancer. In the same direction, plasma levels of neurotransmitters that in general inhibit T cell function are increased during immunosuppresive physiopathological states but low in autoimmunity, while levels of such neurotransmitters with stimulatory role on T cells are increased in autoimmune disorders and decreased in immunodeficiency. The precise knowledge of the dysregulation on concentration and receptors for these molecules into different pathophysiological conditions together with the understanding of precise role of stimulation of each subtype of neurotransmitter receptor on the T cell physiology could strongly help to the design of therapies for the treatment of autoimmunity, immunodeficiency and cancer.. 5-HTRs. =. 5-HT receptors. TCR. =. T cell Receptor. TLRs. =. Toll-like receptors. Tregs.. =. T regulatory cells. REFERENCES [1] [2]. [3] [4] [5] [6]. [7] [8]. [9]. ACKNOWLEDGEMENTS. [10]. This work was supported by grants FONDECYT 3070018 and PFB-16 from CONICYT and Millennium Nucleus on Immunology and Immunotherapy (P04/030-F).. [11]. ABBREVIATIONS ACh. =. Acetylcholine. AChRs. =. ACh receptors. Ag. =. Antigen. APC. =. Ag-presenting cell. ChAT. =. Choline acetyl transferase. CNS. =. Central Nervous System. DCs. =. Dendritic cells. DA. =. Dopamine. DARs. =. DA receptors. EAE. =. Encephalomyelitis autoimmune experimental. Glu. =. Glutamate. Ig. =. Immunoglobulin. iGluRs. =. Ionotropic Glu receptors. MHC. =. Major Histocompatibility Complex. mGluRs. =. Metabotropic Glu receptors. pMHC. =. Peptide-MHC complexes. PAMPs. =. Pathogen-associated molecular patterns. 5-HT. =. Serotonin. Pacheco et al.. [12]. [13]. [14]. [15]. [16]. [17]. [18]. Wong, P.; Pamer, E.G. CD8 T cell responses to infectious pathogens. Annu. Rev. Immunol., 2003, 21, 29-70. Meunier, M.C.; Delisle, J.S.; Bergeron, J.; Rineau, V.; Baron, C.; Perreault, C. 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