Download neuropeptides activate t cells

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Neurotransmitters activate T-cells and elicit crucial functions via
neurotransmitter receptors
Mia Levite1,2
Neurotransmitters are traditionally viewed as nerve-secreted
molecules that trigger or inhibit neuronal functions. Yet,
neurotransmitters bind also their neurotransmitter receptors in
T-cells and directly activate or suppress T-cell functions. This
review focuses only on the activating effects of
neurotransmitters on T-cells, primarily naı̈ve/resting cells, and
covers dopamine, glutamate, serotonin, and few
neuropeptides: GnRH-I, GnRH-II, substance P, somatostatin,
CGRP, and neuropeptide Y. T-cells express many
neurotransmitter receptors. These are regulated by
TCR-activation, cytokines, or the neurotransmitters
themselves, and are upregulated/downregulated in some
human diseases. The context — whether the T-cells
are naı̈ve/resting or antigen/mitogen/cytokine-activated,
the T-cell subset (CD4/CD8/Th1/Th2/Teff/Treg),
neurotransmitter dose (low/optimal or high/excess), exact
neurotransmitter receptors expressed, and the cytokine
milieu — is crucial, and can determine either activation or
suppression of T-cells by the same neurotransmitter. T-cells
also produce many neurotransmitters. In summary,
neurotransmitters activate vital T-cell functions in a direct,
potent and specific manner, and may serve for communicating
between the brain and the immune system to elicit an effective
and orchestrated immune function, and for new therapeutic
avenues, to improve T-cell eradication of cancer and infectious
organisms.
Addresses
1
The School of Behavioral Sciences, The Academic College of Tel-AvivYaffo, Israel
2
Department of Neurobiology, the Weizmann Institute of Science,
Rehovot 76100, Israel
Corresponding author: Levite, Mia ([email protected])
Current Opinion in Pharmacology 2008, 8:460–471
This review comes from a themed issue on
Immunomodulation
Edited by Mia Levite and John Gordon
potently activate vital human T-cell functions needed for
the T-cells to perform their specialized tasks, such as
cytokine secretion, adhesion to extracellular matrix
(ECM), chemotactic migration and homing into specific
organs and eradication of infectious organisms and cancer
cells ([1,2,3,4,5,6,7], most of the additional studies
cited in this review, and others) (Tables 1 and 2, Figures
1–3). In fact, both activating and suppressing effects of
neurotransmitters on T-cells were reported, depending
on the neurotransmitter itself, as well as on all the
parameters discussed below and shown schematically
in Figure 4.
For maintaining clarity, brevity, and focus in this review,
and because of space limitations, the present review will
deal with only one type of immune cells: T-cells, and
cover only the activation of these cells by certain neurotransmitters. To stay away from misleading generalizations, the review will NOT elaborate on various other
effects of either the same or other neurotransmitters on
diverse immune cells (such as B cells, dendritic cells,
stem cells, neutrophils, macrophages, natural killer monocytes, mast), and will NOT cover the suppressive effects
of some neurotransmitters on T-cell function.
Tables 1 and 2 cover for example three ‘small’ neurotransmitters: dopamine, glutamate and serotonin, and
four peptidergic neurotransmitters (i.e. neuropeptides):
GnRH-I, GnRH-II, Substance P, and Somatostatin and
show: first, their main function in the brain; second,
their known receptors in the body; third, their receptors
expressed in T-cells; fourth, some of the T-cell functions these neurotransmitters (or their receptor agonists) activate, when they bind naı̈ve/resting T-cells;
and fifth, potential relevance to human disease, i.e.
the reported abnormal expression of certain neurotransmitter receptors in T-cells, or the abnormal T-cell
response to these neurotransmitter, reported in few
human diseases.
Available online 23rd June 2008
1471-4892/$ – see front matter
# 2008 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coph.2008.05.001
Introduction
It is undoubtedly clear now that many neurotransmitters
can bind to their neurotransmitter receptors expressed
not only in various ‘classical’ target cells within the central
or peripheral nervous system, but also in T-cells, and can
Current Opinion in Pharmacology 2008, 8:460–471
Neurotransmitters
A substance is conventionally viewed as a neurotransmitter, if the following four criteria are met: first, it is
synthesized in neurons; second, it is present in the
presynaptic terminal and released in amounts sufficient
to exert a defined action on the postsynaptic neuron or
effector organs; third, when administered exogenously (as
a drug) in reasonable concentrations, it precisely mimics
the action of the endogenously released transmitter; and
fourth, a specific mechanism exists for its removal from its
site of action (the synaptic cleft).
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Neurotransmitters activate T-cells Levite 461
Table 1
Three examples of neurotransmitters that can directly activate naı̈ve/resting human T-cells: Their main function and receptors in the
brain, receptors in T-cells, activating effects on T-cells, and abnormal expression/function of the receptors in T-cells in human diseases
Dopamine
Dopamine effects in the brain: Regulation of movement and involvement in psychoses
Dopamine receptors expressed in the brain: Dopaminergic receptors D1, D2, D3, D4, D5
Dopamine receptors expressed in various T-cells: Primarily D3 and D2, but also D1/5 and D4, depending on the T-cell subpopulation and
activation state [7,10,15,16,–21,42]
Among the human T-cell functions activated/enhanced by Dopamine:
(1) Induction of integrin-mediated adhesion to fibronectin of human T-cells [10]; (2) Production of TNFa mRNA and secretion of TNFa (primarily via
D3R) [7]; (3) Production of IL-10 mRNA and secretion of IL-10 (primarily via D2R) [7]; (4) Induction of integrin-mediated adhesion of naı̈ve CD8+
T-cells to fibronectin and ICAM-1 [21]; (5) Induction of chemotactic responses of naı̈ve CD8+ T-cells and their attraction to the peritoneal cavity [21];
(6) Induction of Th2 to Th1 shift in cytokine secretion upon stimulation of activated T-cells by dopaminergic agonist [24]; (7) Suppression of
regulatory T-cells (Treg) which subsequently releases Treg inhibition on T effector cells [13,22]
Abnormal expression or function of Dopamine receptors in T-cells in human diseases:
Schizophrenia [23–25]; Parkinson’s disease [27]; Alzheimer’s disease [17]; Migrane (cited within [17]) and Multiple sclerosis [31]
Glutamate
Glutamate effects in the brain: The brain’s primary excitatory neurotransmitter, involved in affective, sensory, and motor function, learning,
memory, cognition, and synaptic plasticity
Glutamate receptors expressed in the brain: Ionotropic glutamate receptors: NMDA, AMPA, and Kainite; Metabotropic glutamate receptors
mGluR1, 2, 3, 4, 5, 6, 7
Glutamate receptors expressed in various T-cells: Ionotropic: AMPA GluR3 in normal, leukemia and encephalitogenic anti-MBP T-cells from
mice, healthy individuals and MS patients [6,11,33]; AMPA and Kainate [32]; Metabotropic: mGlu1R, mGlu5R [43]
Among the human T-cell functions activated/enhanced by Glutamate:
(1) Induction of T-cell adhesion to fibronectin and laminin [6]; (2) Induction of chemotactic migration of normal naı̈ve peripheral T-cells towards
SDF-1 [6]; (3) Induction of calcium signals and c-jun and c-fos gene expression, via group I metabotropic glutamate receptors [38]; (4) Positive
modulation Kv1.3 channel gating, causing currents to activate faster and at significantly more hyperpolarized potentials, hence rendering the T
lymphocyte readily responsive to immune stimuli [37]; (5) Enhancement of T lymphocyte proliferation to MBP and MOG and the chemotactic
migration of T-cells in MS patients and control individuals. Higher GluR3 expression and higher activating effect of glutamate on T-cells of MS
patients during relapses were reported [33].
Abnormal expression or function of Glutamate receptors in T-cells in human diseases:
Multiple sclerosis [33]; ALS [36]
Serotonin
Serotonin effects in the brain: Regulation of emotion, anxiety, agitation, and gastrointestinal function
Serotonin receptors expressed in the brain: Serotonergic 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4,
5-HT5, 5-HT6, 5-HT7
Serotonin receptors expressed in various T-cells: Serotonergic 5HT1, 5HT1a, 5-HT(1B), 5-HT(2A), 5-HT3, 5-HT3A, 5-HT7 [39,44,45]
Among the human T-cell functions activated/enhanced by Serotonin:
(1) Induction of Na+ influx [46]; (2) Induction of IL-16 secretion from CD8+ (not CD4+) T-cells [40]; (3) Enhancement of proliferation and IL-2
production in response to Con A [39]; (4) Induction of ERK1/2 phosphorylation in naı̈ve T-cells via 5-HT(7) [45]; (5) Potentiatation of T-cell activation,
via elevated [Na(+)](i) and activation of PKC-dependent PLD pathway [47]; (6) Increased proliferation and mRNA for IL-2 and IFN-g in PHAstimulated in lymphocytes from HIV-seropositive subjects [48]; (7) Injection of a serotonin receptor agonist to HIV-seropositive subjects increased:
CD4 T-cells, CD4/CD8 ratio, T-cell proliferation to mitogen and expression of IL-2R (Hofmann et al., 1996)
Abnormal expression or function of Serotonin receptors in T-cells in human diseases: HIV [48]
Neurotransmitters fall into one of three chemical
categories:
(1) Amino acids: among them Glutamate, Glycine, and
g-aminobutyric acid (GABA).
(2) Biogenic amines: among them Dopamine, Norepinephrine, Epinephrine and Serotonin.
(3) Peptidergic neurotransmitters termed neuropeptides:
among them Somatostatin, Substance P, Neuropeptide Y, Opioids, Gonadotropin releasing hormone
(GnRH): GnRH-I and GnRH-II, Calcitonin generelated peptide (CGRP), Thyrotropin releasinghormone (TRH), Corticotropin releasing hormone
(CRH), Vasoactive intestinal polypeptide (VIP),
Neurotensin, Bombasin, Prolactin, Galanin, Motilin,
and many others. The peptidergic neurotransmitters
are well known to exert physiological effects at
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substantial distances from their sites of release, with
clear implication for the functional interactions
between nerve fibers and immune target cells.
Neurotransmitters have a very wide spectrum of activities
via which they affect a kaleidoscope of body functions,
some shown in Tables 1 and 2. Many neurotransmitters
and/or their analogues have medicinal properties, serve as
drugs for various diseases, and are subject of extensive
pharmacological studies.
Where can T-cells ‘meet’ neurotransmitters?
T-cells may be exposed to neurotransmitters in the:
(a) Brain — since activated T-cells, and to a lesser extent
naı̈ve/resting T-cells, regularly transmigrate into the
Current Opinion in Pharmacology 2008, 8:460–471
462 Immunomodulation
Table 2
Four examples of neuropeptides (peptidergic neurotransmitters) that can directly activate naı̈ve/resting human T-cells: Their primary
function and receptors in the brain, receptors in T-cells, and some of their activating effects on T-cells
GnRH-I and GnRH-II
GnRH-I and GnRH-II effects in the brain: GnRH-I: Stimulates pituitary synthesis of LH and FSH. The chief hormone orchestrating reproductive
events; GnRH-II: Multiple, under investigation
GnRH receptors expressed in the brain: GnRH-I R; GnRH-II R identified thus far only in non-human primates. The human GnRH-II R gene is
disrupted
GnRH receptors expressed in various T-cells: GnRH-I R and a postulated GnRH-II R which is different than GnRH-I R (i.e. GnRH-II induced
effects are not blocked by GnRH-I R antagonists) [5]
Among the T cell functions activated/enhanced by GnRH-I and GnRH-II:
(1) Increase in IL-2 receptor-positive cells and in the basal proliferative activity of splenocytes and thymocytes (Batticane et al., 1991); (2) Injection
of GnRH-I agonist increases CD8+ T-cell levels and proliferation to a variety of mitogens [49]; (3) Induction by GnRH-I and GnRH-II of de novo T cell
gene expression and of cell surface expression of 67-kDa laminin receptor [5]; (4) Induction by GnRH-I and GnRH-II of T-cell adhesion to laminin
[5]; (5) Induction by GnRH-I and GnRH-II of T-cell chemotactic migration towards SDF-1 [5], (6) Augmentation of T-cell homing in vivo into the
spleen and bone marrow [5], (7) Increase in IFNg production and in response to IFNg; decrease in IL-4 production (Dixit et al., 2003); (8) Increase
in vivo of: CD3+CD69+, CD3+CD25+, and CD3+DR+ lymphocyte subpopulations (decrease CD4+ and CD25+ T-cells) (Ho et al., 1995)
Substance P
Substance P effects in the brain: In CNS: regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm,
neurotoxicity, nausea/emesis and pain
Substance P receptors expressed in the brain: NK1, NK2, NK3
Substance P receptors expressed in various T-cells: NK1 receptor ([50] & McCormack, 1996)
Some of the T cell functions activated/enhanced by Substance P:
(1) Stimulation of human T-cell proliferation ([50] and Payan et al., 1984); (2) Stimulation of IL-2 production, via the NK1 receptor; (3) Induction of
atypical secretion of IL-2 and IFN-g by Th2 antigen-specific T cell lines and clones [1,3]; (4) Increase of proliferation, IL-2 production and CD4+
CD25+ and CD4+ RT1B MHC class II molecule via the NK1 receptor (Santoni et al., 2002); (5) In vivo: stimulation of efferent lymph flow and the
output into efferent lymph of both small recirculating and blast lymphocytes; Increase and prolongation of in vivo CD4 T-cell output from lymph
nodes, associated with a depressant effect on the output of CD8 T-cells (and B cells) (Moore et al., 1990); (6) Enhancement of T cell adhesiveness to
endothelial cells, via enhancement of LFA-1/ICAM-1 interactions and induction of T-cell chemotaxis (Vishwanath et al., 1996); (7) Increase in T-cell
proliferation by an autocrine effect of endogenous substance P produced by T-cells; the effect is mediated by NK1 receptors (Lambrecht et al.,
1999); (8) Induction of T-cell chemotaxis, via the NK1 receptor (Hood et al., 2000); (9) Induction of proliferation, CD25 expression and IL-2
production, and rescue of apoptosis (Santoni et al., 2002)
Somatostatin
Somatostatin effects in the brain: Regulates the endocrine system and affects neurotransmission and prolifeartion by inhibiting the release of
numerous secondary hormones
Somatostatin receptors expressed in the brain: SSTR1, SSTR2, SSTR3, SSTR4, SSTR5
Somatostatin receptors expressed in various T-cells: Primarily SSTR2 and SSTR3, SSTR1, SSTR4. SSTR5 expression was reported selectively
in activated T-cells (Talme et al., 2001; SSTR2, Elliott et al., 1999, Solomou et al., 2002)
Some of the T-cell functions activated/enhanced by Somatostatin:
(1) Induction of integrin-mediated adhesion to fibronectin, [4] and to a certain extent also to collagen type IV and laminin, via SSTR2 and SSTR3
(Talme et al., 2001); (2) Induction of typical and atypical secretion of IL-2, IFN-g, IL-4 and IL-10 by Th0, Th1 and Th2 antigen-specific T cell lines and
clones [10]; (4) Induction of IL-2 secretion and proliferation [23,89]
For other effects of somatostatin on T-cells read: Ferone et al. (2004), Krantic et al. (2000), ten Bokum et al. (2000)
CNS across the blood brain barrier, under physiological and pathological conditions.
(b) Lymphoid organs — as all primary and secondary
lymphoid organs, among them the thymus, spleen,
lymph nodes, bone marrow and gut, are massively
innervated by nerves which release a variety of
neurotransmitters and neuropeptides [8,9].
Furthermore, within these lymphoid organs, there
are direct contacts between nerve terminals containing neurotransmitters, and individual immune cells,
among them T-cells and B-cells and mast-cells
[8,9].
(c) Blood — since both fenestrated and non-fenestrated
blood capillaries are intensely innervated by nervesecreting neurotransmitters, thus providing conditions for direct contacts between neurotransmitters
and blood-borne T-cells in health and disease.
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(d) All the other innervated body organs — since all these
contain neurotransmitters as well as T-cells that pass
through for routine immune surveillance.
Collectively, all the above indicate that various neurotransmitters may encounter and affect T-cells in everyday
life, in almost every site of the body, and in almost every
context of health and disease.
T-cells produce endogenous
neurotransmitters and can be affected by
them in an autocrine/paracrine manner
Numerous interesting and solid studies show that T-cells
(and other immune cells) can in fact produce and secrete
various endogenous neurotransmitters, either spontaneously or after induction by external stimuli. Some of
the neurotransmitters produced by T-cells are: Dopamine,
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Neurotransmitters activate T-cells Levite 463
Figure 1
Schematic representation showing the various features and functions of normal resting peripheral human T-cells that are activated or modulated by
dopamine itself, or by selective dopamine-receptor agonists.
Epinephrine, Norepinephrine, Acetylcholine, Serotonin,
Somatostatin, VIP, CGRP, GnRH-I, GnRH-II, and others.
T-cells may also be affected by some of their endogenously produced and exogenously secreted neurotransmitters in an autocrine and paracrine manner (e.g. [10]), yet
only if the concentration of the respective neurotransmitter is appropriate.
Finally, I speculate that T-cells may use their own
neurotransmitters not only to ‘talk’ to themsleves, but
also to ‘talk’ to other cells, mainly to neurons and glia
cells, when they enter the brain and ‘need’ to communicate and cooperate with these CNS-resident cells, for
example, during viral infection within the CNS.
T-cells express specific receptors for various
neurotransmitters, and these are dynamically
regulated by TCR-activation, cytokines, the
neurotransmitters themselves, and other
factors
Neurotransmitters exert all either excitatory or inhibitory
effects on their targets by binding to their cognate
receptors expressed in target cells within the nervous
system. Each neurotransmitter has a broad family of
receptors. The families of neurotransmitter receptors
expressed in the nervous system for some of the relevant
neurotransmitters and neuropeptides discussed herein,
are shown in Tables 1 and 2, respectively. These tables
also show the main neurotransmitter receptors expressed
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in T-cells, focusing primarily on published evidence for:
first, the existence of these receptors at the protein level
(not only mRNA, which may or may not be translated)
and second, the functional response of these neurotransmitter receptors to the natural neurotransmitter itself
(not only to synthetic and somewhat artificial neurotransmitter agonists).
Interestingly, the expression of the neurotransmitter
receptors in T-cells seems to be very dynamic, and can
change dramatically in response to different molecules
and processes among them:
(a) T-cell receptor (TCR) activation. TCR-activation,
that is induced naturally and specifically by viral/
bacterial/parasite/cancer antigens, and can be
mimicked artificially by mitogens (e.g. phorbol
esters) and anti-CD3 and anti-CD28 antibodies,
may dramatically affect the expression of a given
neurotransmitter receptor on the T-cell membrane.
For example, we recently described a striking
example: the glutamate receptor of the AMPA GluR3
subtype (GluR3) is highly expressed in peripheral
naı̈ve/resting human T-cells (60–90% GluR3
positive) of all healthy individuals tested, yet
eliminated completely from the T-cell surface upon
TCR-activation [11] (Figure 2). Going deeper into
the mechanism, we revealed that it is granzyme B, the
key proteolytic enzyme which is routinely released
from TCR-activated T-cells, that cleaves GluR3 from
Current Opinion in Pharmacology 2008, 8:460–471
464 Immunomodulation
Figure 2
Glutamate receptor of the AMPA subtype 3, GluR3, is highly expressed in resting human T-cells, but not in TCR-activated cells, as the latter release the
proteolytic enzyme granzyme B which cleaves GluR3 from their surface [6]. (a–c) Evidences for the presence in T-cells of high levels of GluR3, which is
identical in sequence to the brain’s GluR3. (a) GluR3 RT-PCR in normal naı̈ve human peripheral T-cells, human T leukemia line and human T helper
clone, and in total brain as positive control [6]. The GluR3 RT-PCR amplification products in T-cells are of the expected molecular weight for each set
of primers respectively (E4-E9 632 bp and E3-E6 516 bp) [6]; (b) Double immunofluoresence staining and flow cytometry of naı̈ve normal human
T-cells for GluR3 (FITC) and TCR (PE), showing 74% GluR3+ TCR+ double positive cells [6]. (c) GluR3-specific immunostaining staining and confocal
microscopy of naı̈ve normal human T-cells (Levite et al., paper in preparation). (d–e) Once T-cells become activated via their T-cell receptor (TCR) by
viral/bacterial/parasite/cancer antigens, they characteristically release Granzyme B, a very potent and important proteolytic enzyme. Granzyme B
cleaves GluR3 from the T-cell surface, resulting in the complete elimination of this glutamate receptor from the T-cell membrane for some 48 h. After
this lag period, GluR3 expression is restored [6]. Cleaved GluR3 portions, containing the immunogenic GluR3B peptide are released to the
extracellular milieu. We suggest that this event, if chronic, drives the production of pathogenic GluR3B autoantibodies found in epilepsy patients (see
the discussion in [6], the Refs cited therein, and our papers on glutamate receptor autoantibodies and ‘Autoimmune Epilepsy’) [51].
such activated cells, leading to its disappearance from
the cell surface for 48 h [11] (Figure 2).
(b) Cytokines. Certain cytokines, alike IL-2, can change
the expression of neurotransmitter receptors in Tcells.
(c) The neurotransmitter itself. Alike in neurons, a
neurotransmitter can regulate (usually downregulate)
the expression of its own receptors in T-cells.
activate many T-cell functions in a powerful and rapid
manner. Table 1: for dopamine, glutamate, and serotonin
and Table 2: for the neuropeptides GnRH-I, GnRH-II,
Substance P and Somatostatin (other relevant and important neuropeptides, including NPY and CGRP [3,4], are
unfortunately not covered in this review because of space
limitation) present examples of neurotransmitters that by
themselves activate T-cell function. Herein, only two of
these neurotransmitters will be further discussed: dopamine and glutamate.
Many neurotransmitters can trigger T cell
function
Dopamine
The data accumulated thus far show that various neurotransmitters bind to their receptors in T-cells and can
Dopamine (Table 1) is one of the principal neurotransmitters in the central nervous system involved in several
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Neurotransmitters activate T-cells Levite 465
Figure 3
Schematic representation showing the various features and functions of normal resting peripheral human T-cells that are activated or modulated either
by glutamate itself, or by selective glutamate/AMPA receptor agonists.
key functions such as behavior, control of movement,
endocrine regulation, and cardiovascular function. The
secondary lymphoid tissues are highly innervated by
sympathetic nerve fibers that store dopamine at high
contents, and lymphocytes also produce dopamine
[12,13,14]. Dopamine signals via five different seventransmembrane G-protein-coupled receptors termed D1–
D5 dopamine receptors, some of which (particularly of
the D2 subclass) represent the primary therapeutic target
in a number of neuropathological disorders, including
schizophrenia, Parkinson’s disease, and are expressed
in Huntington Chorea.
Dopamine triggers T-cell function via its dopamine receptors
Dopamine-receptors D2, D3, D4 and D5 are expressed in
T-cells ([7,10,15,16,21], see also Table 1). Furthermore, these dopaminergic receptors are genuinely functional, because various T-cell functions are affected upon
binding of dopamine or dopaminergic agonists to T-cells.
The T-cell features and functions activated by dopamine
or by highly selective dopamine D2 and D3 receptor
agonsists appear in Table 1 and are shown schematically
in Figure 1. For example, we reveled that dopamine on its
own can activate human normal naı̈ve peripheral T-cells
and trigger their adhesion to fibronectin [10], a major
glycoprotein of the extracellular matrix (ECM), via activation of 4b1 a5b1 integrin moieties. Such T-cell
adhesion is critical for trafficking and extravasation of
T-cells across blood vessels and tissue barriers [10].
Using seven dopaminergic agonists and antagonists
highly selective for the different dopamine subtypes,
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we further found that the dopamine-induced T-cell
adhesion was mediated via the D3R and D2R [10].
Testing dopamine in a broad concentration range of
10 16 to 10 4 M, we found that 10 nM was within the
optimal range for activating T-cells [10].
In a subsequent confirming study, Watanabe et al. [21]
found that the D3R was the predominant subtype of
dopamine-receptors in the secondary lymphoid tissues
and selectively expressed by naı̈ve CD8+ T-cells from
both humans and mice. Dopamine selectively induced
the chemotactic migration of naı̈ve CD8+ T-cells, and was
highly synergistic with CCL19, CCL21, and CXCL12.
Dopamine also selectively induced adhesion of naı̈ve
CD8+ T-cells to fibronectin and ICAM-1 by the activation
of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naı̈ve CD8+ T-cells into the
peritoneal cavity. Treatment of mice with a D3 antagonist
reduced homing of naı̈ve CD8+ T-cells into lymph nodes
[21].
Dopamine can also induce T-cell cytokine secretion.
Indeed, we found that dopamine on its own induced a
significant increase in TNFa and IL-10 secretion by
naı̈ve resting normal-human T-cells, and induced 5fold elevation of the corresponding TNFa and IL-10
mRNA levels (without affecting IFNg and IL-4) [7].
Interestingly, dopamine-induced TNFa upregulation
was evident 24 hours after dopamine stimulation, and
was mediated primarily by D3R, while IL-10 upregulation was evident after 72 hours, and was mediated primCurrent Opinion in Pharmacology 2008, 8:460–471
466 Immunomodulation
Figure 4
It’s a matter of context: The context determines the final effect of a given neurotransmitter on a given T-cell function. The schemes in A-D show the
most important factors that determine whether a specific neurotransmitter would activate or suppress a given T-cell function: (a) The activation state of
the T-cells: this has a major impact on the specific neurotransmitter receptors expressed on the cell surface of T-cells, and on the response of these Tcells to the neurotransmitter. Naı̈ve/resting resting T-cells are often activated by a given neurotransmitter, while TCR-activated or cytokine-activated Tcells are often suppressed by the very same neurotransmitter. (b) The specific neurotransmitter receptors expressed on the T cells. Each
neurotransmitter has a broad family of cognate receptors, which all bind the native neurotransmitter, but respond somewhat differently, due to their
different characteristics. (c) The neurotransmitter dose: many neurotransmitters affect T-cell function at an optimal low range of 10 10 to 10 8 M.
Higher concentration may be nonproductive, suppressive or even toxic [6,33,37,39]. (d) The T-cell subtype: Different T-cells subpopulation can
respond differently to the same neurotransmitter. CD4+ react differently than CD8+ T-cells [40], and so do Th1 and Th2 T-cells [14,41], and Teff and
Treg cells [13]. (e) Other neurotransmitters released concomitantly from the same nerve endings or others. T-cells exposed to one neurotransmitter
or neuropeptide would respond differently than T-cells exposed simultaneously to more than one neurotransmitter or neuropeptide released from the
same neuron. Examples of neuroactive peptides coexisting with other neurotransmitters in the same neurons are: (1) Dopamine and Cholecystokinin or
Neurotensin; (2) Serotonin and Substance P or TRH or Enkephalin; (3) Norepinephrine (noradrenaline) with Galanin, Enkephalin, or Neuropeptide Y; (4)
Epinephrine (adrenaline) with Neuropeptide Y or Neurotensin; (5) GABA with Somatostatin or Cholecystokinin or Neuropeptide Y; (6) Acetylcholine with
VIP or Substance P. In addition to the above, some neurons make several different neuropeptides. For instance, Vasopressin coexists with dynorphin
and galanin or with CRF. Oxytocin co-exists with enkephalin, dynorphin and cholecystokinin. (f) The cytokine milieu. The specific cytokines present
around the T-cells once a neurotransmitter is released in their vicinity, can markedly affect the final effect of this neurotransmitter on these cells.
arily by D2R. This study showed that dopamine has an
unique ability to trigger a selective secretion of either
TNFa only (via D3R), or IL-10 only (via D2R) or both
(via D1/D5R) [7]. This dopamine-induced effect sharply
contrasts with ‘classical’ TCR-activation, that leads to a
robust yet nonselective secretion of all the T-cell cytokines. As such, dopamine-induced T-cell cytokine
secretion may have important implications in fighting
pathologies that are either mediated or can be cured by
IL-10 or TNFa.
Dopamine can probably also activate T-cell function
indirectly, by suppressing T-regulatory cells (Treg), as
suggested recently [13,22]. Here, the endogenous catecholamines act by autocrine/paracrine loop, via dopaminergic receptors and pathways, to downregulate Treg
function [13]. The effect is mediated primarily by D1
receptors [13].
Current Opinion in Pharmacology 2008, 8:460–471
Taken together, all the above mentioned effects, and
those described in Table 1 and Figure 1, show that
dopamine by itself can bind to naı̈ve/resting peripheral
T-cells, and induce T-cell adhesion, chemotactic
migration, attraction and homing into specific organs,
cytokine secretion, and additional T-cell functions. All
these suggest that dopamine is very important not only for
its well-known ‘classsical’ effects (see Table 1), but also
for delivering signals from the brain to T-cells, needed for
effective, proper, regulated, and orchestrated immune
responses.
Having said that, and focused herein only on the activating effects on dopamine on T-cell function, it should
nevertheless be mentioned that dopamine can also suppress some T-cell functions and features, primarily proliferation and cytotoxicity, mainly when it interacts with
activated T-cells (rather than with naı̈ve/resting T-cells).
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Neurotransmitters activate T-cells Levite 467
Relevance of the dopamine-receptors in T-cell to human
diseases
Abnormal expression of dopamine-receptors in lymphocytes/T-cells, or abnormal response of dopaminergic
receptors in lymphocytes/T-cells, was reported in Schizophrenia [23–25], Parkinson’s disease, [26,27], Alzheimer’s
disease [17], Migraine [28], HIV [29,30], and Multiple
Sclerosis [31]. Unfortunately, some of these studies studied only the presence of abnormal receptor mRNA
levels rather than the functional receptor itself. Thus,
further studies are needed before the pathological and
pharmacological significance of these potentially exciting
findings can be fully evaluated.
Glutamate
Glutamate (Table 1) is the brain’s primary excitatory
neurotransmitter, involved in affective, sensory, and
motor function, as well as in learning, memory, cognition,
and synaptic plasticity. Glutamate signals though two
broad families of glutamate receptors, consisting of the
ionotropic (ion channels) glutamate-receptor, and the
G-protein-coupled metabotropic glutamate-receptors.
The ionotropic glutamate-receptors are subdivided into
AMPA, Kainate, and NMDA glutamate-receptors, and in
each, there is yet some further subdivision to individual
receptors having different numbers. The metabotropic
glutamate receptors are also subdivided into mGluR1 to
mGluR7.
Glutamate triggers T-cell function via its glutamate-receptors
Human T-cells express several types of glutamate-receptors, and glutamate has various effects on T cell function
[32,6,11,33,34–38]. Table 1 and Figure 3 list and cite
some of the glutamate-induced T-cell functions and
features.
In a recent study we described for the first time, that
normal human T-cells, human T-leukemia line, and the
mouse anti-myelin basic protein (MBP) 87–99 T-cells
(which induce experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis
(MS)), express very high levels of glutamate receptor
GluR3 [6]. The multiple methodologies used for showing GluR3 expression in T-cells (Figure 2a–c) include:
GluR3-specific RT-PCR and sequencing, establishing
identity between the T-cell GluR3 and the authentic
brain GluR3, Western blot, and GluR3 cell-surface
expression, as revealed by immunofluorescence-staining, flow-cytometry, and confocal microscopy [6].
Furthermore, glutamate in the absence of any additional
molecule, induced integrin-dependent adhesion to
laminin and fibronectin, and chemotactic migration
toward the chemokine SDF-1 [6] (Figure 2d,e). The
effects of glutamate were mimicked by AMPA (glutamate/AMPA receptor-agonist) and blocked by CNQX
and NBQX (glutamate/AMPA receptor-antagonists).
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Testing glutamate in a very broad concentration range,
we found that glutamate-induced T-cell activation was
evident in an optimal conc. of 10 nM, which is exactly
the concentrations of glutamate within the brain extracellular fluid. Taken together, the high expression of
GluR3 in T-cells, and the ability of glutamate to activate
T-cell functions in its physiological concentration within
the brain, could be of importance in many physiological
and pathological situations, among them: first, T-cell
transmigration into the CNS across laminin-containing
capillary endothelial cells that form the blood–brainbarrier and second, T-cell mediated autoimmune diseases, especially MS [6].
Surprisingly, in a subsequent study [11], we further
found that the glutamate receptor GluR3 is completely
eliminated from the cell surface of the TCR-activated
cells, and that this is because of proteolytic cleavage of
GluR3 by granzyme B released by the TCR-activated
cells. This is shown schematically in Figure 2. In parallel
to losing intact GluR3, TCR-activated cells also lose
glutamate-induced adhesion to laminin [6]. Thus, glutamate, via GluR3, may activate only resting, but not
TCR-activated cells [6].
Gallart et al. have recently shown that human dendritic
cells undergoing maturation and in contact with T-cells,
release significant amounts of glutamate, and that after
productive antigen presentation, the metabotropic glutamate-receptor 1 is expressed in T-cells and mediates an
enhanced T-cell proliferation, and secretion of Th1 and
proinflammatory cytokines [34].
The stimulation of group I metabotropic glutamatereceptors also evokes calcium signals and c-jun and
c-fos gene expression in human T-cells, thus activating
multiple downstream signaling regulating important
T-cell functions [38].
Glutamate, at concentrations within its normal plasma
levels, and via metabotropic glutamate receptors also
positively modulates the channel gating of Kv1.3 [37],
a key voltage-gated potassium ion channel in T-cells [2],
causing a faster current activation at significantly more
hyperpolarized potentials, hence rendering the T-cells
readily responsive to immune stimuli [37].
These and other glutamate-induced T-cell activating
effects are mentioned in Table 1 and Figure 3.
Relevance of glutamate-receptors in T-cell to human
diseases
Multiple sclerosis
Sarchielli et al. [33] showed recently that T-cells of
control subjects and MS patients express both the
mRNA and the GluR3 receptor protein, in line with
Current Opinion in Pharmacology 2008, 8:460–471
468 Immunomodulation
GluR3 expression shown previously in murine antiMBP 87–99 T-cell line [37]. Excitingly, an upregulation of the GluR3 expression during relapse, and in
patients with neuroradiological evidence of disease
activity, was revealed [33]. Furthermore, glutamate
and AMPA, at concentrations of 10 nM to 10 mM
enhanced T-cell proliferation to MBP and MOG, and
the chemotactic migration of T-cells of both controls
and MS patients. In the latter group, significantly
higher proliferation values in response to glutamate
were found in patients assessed during relapse and in
those with gadolinium (Gd)+ enhancing lesions on
MRI. Together, MS patients during relapses with evidence of disease activity on MRI, had higher GluR3
expression in their T-cells and glutamate affected these
cells to a greater extent [33]. These interesting findings are in perfect agreement with the original suggestions raised when GluR3 was first detected in
encephalitogenic anti-MBP T-cells [6], and support
the idea that glutamate-induced activation of MSassociated T-cells may indeed play a vital role in
this disease. This topic surely calls for further investigation.
Autoimmune epilepsy
We recently suggested that the cleavage of glutamate
receptor GluR3 from the T-cell surface by granzyme B,
upon TCR-activation, and the release of immunogenic
GluR3B peptide to the extracellular milieu (especially if
occurring in a continuous manner, for example in a
chronic infection), could be the first step leading to
the production of neuropathogenic GluR3B autoantibodies, found in some epilepsy patients (see the Discussion in [6], the relevant Refs cited therein, and our
papers on ‘Autoimmune Epilepsy’) [51].
It is a matter of context: crucial factors can
determine whether a given neurotransmitter
would activate or rather suppress a given
T-cell function
An important take-home message from the study on the
effects of neurotransmitters on T-cells, should be that a
given neurotransmitter is rarely exclusively stimulatory or
inhibitory, when it comes to its effects on T-cells. I would
argue that the findings thus far show that often the very
same neurotransmitter can be both activating and suppressing! It all depends on the absolutely crucial factors
that determine the functional outcome, shown schematically in Figure 4a–f. These include:
(a) The activation state of the T-cells. Naı̈ve/resting
T-cells are often activated by a given neurotransmitter, while TCR-activated or cytokine-activated
T-cells are often suppressed by the very same
neurotransmitter.
(b) The subtype of neurotransmitter receptors expressed
on the target T-cells. Each neurotransmitter has a
broad family of receptors, which all bind the parent
neurotransmitter, but respond somewhat differently,
because of some different characteristics and signaling pathways. Naı̈ve/resting T-cells often express
a different composition of neurotransmitter receptors
than activated T-cells [6,33,37,39].
(c) The neurotransmitter dose. Many neurotransmitters
affect T-cell function at an optimal low dose range of
10 10 to 10 8 M. Higher concentration may be
either nonproductive, suppressive or even toxic
[6,33,37,39].
(d) The T-cell subpopulation being stimulated. CD4+
and CD8+ T-cells may respond differently to
neurotransmitters [40], and so do Th1 and Th2 cells
[14,41] and regulatory and effector T-cells [13].
Are the interactions of T-cells with
neurotransmitters beneficial or detrimental,
first for the cells themselves and second for
the overall health of the body?
Indeed, different T-cell subpopulations often express
different receptor subtypes for the same natural neurotransmitter.
I would provocatively argue that the answer to these
questions is NOT dictated by the neurotransmitter itself
(which has ‘fixed’/conserved identity), but rather by the
target T-cells and the context, see Figure 4. Thus, if
the T-cells are normal and healthy, their activation by a
given neurotransmitter will most probably be beneficial
both for the T-cells themselves and for the entire body,
as it will improve the beneficial performance of these
‘good’ T-cells. By contrast, if the T-cells are detrimental,
alike cancer T-cells, that is, T-leukemia and T-lymphoma, or autoimmune T-cells, alike in MS and other
T-cell-mediated autoimmune diseases, their activation
by a neurotransmitter will still be beneficial for these
detrimental T-cells, but this time bad for the entire
body, since it would aggravate the T-cell-mediated
pathogenicity.
(e) The cytokine, chemokine, and growth factors milieu.
These may change dramatically the effect of a given
neurotransmitter on a given T-cell population, as
shown by published and yet unpublished data.
(f) Other neurotransmitters released concomitantly.
Nerve endings often contain both a conventional
neurotransmitter (such as glutamate, GABA, or
dopamine) and one or more neuropeptides, as shown
schematically in Figure 4e. There are many such
couples of neuroactive peptides coexisting with other
neurotransmitters, and specific examples are listed in
the legend for Figure 4e. The neuropeptides are
generally packaged in large dense-core vesicles, and
the coexisting neurotransmitters in small synaptic
vesicles. The location within the neuron and the
Current Opinion in Pharmacology 2008, 8:460–471
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Neurotransmitters activate T-cells Levite 469
release of the large and small vesicles are different.
Clearly, one may envision different contexts and
different outcomes: first, T-cells exposed only to one
neurotransmitter or one neuropeptide; second, T-cells
exposed simultaneously to a given neurotransmitter
and a given neuropeptide, or to one after the other.
Each of the above parameters can dictate whether a
specific neurotransmitter will activate, suppress or rather
not affect at all a given T-cell function. Variations in the
above parameters that define the context, are most probably the basis for some of the contradictory results
reported in the literature, for example where the
term ‘inhibitory neuropeptide’ was assigned to a given
neuropeptide that, at physiological concentrations, can in
fact activate T-cell function in a direct and profound
mode.
natural neurotransmitters activate T-cells and improve
their function in vitro and in vivo, also opens up novel and
safe ways by which the pharmacological world could take
advantage of it to fight some human diseases, primarily
cancer and infectious diseases. Indeed, an especially
attractive therapeutic avenue is to activate T-cells by
natural neurotransmitters ex vivo, for improved adoptive
T-cells immunotherapy of cancer. We are currently moving forward to test this exciting therapeutic option.
Acknowledgements
I thank Yonatan Ganor for his contribution to the preparation of the tables.
References and recommended reading
Papers of particular interest, published within the period of review,
have been highlighted as:
of special interest
of outstanding interest
Summary and concluding remarks
The large body of evidence outlined in this review
indicates that some of the ‘classical’ neurotransmitters,
alike dopamine, glutamate and serotonin, and numerous
neuropeptides among them Substance P, GnRH-I and II,
Neuropeptide Y, CGRP and Somatostatin have the ability to bind to their cognate receptors in T-cells and
activate pivotal T-cells functions.
Among the T-cell functions and features that are triggered/elevated by neurotransmitters (see Tables 1 and 2
and Figures 1 and 3) are: T-cell adhesion, chemotactic
migration, homing into solid organs, cytokine secretion,
proliferation, cytotoxicity, ion currents, the levels of
intracellular Ca2+, the level of surface expressed receptors, de novo gene expression, mRNA levels of various
proteins, signal transduction, and others. The expression
of the neurotransmitter receptors in T-cells is by no
means constant: it can be changed dramatically by
TCR-activation, cytokines, the neurotransmitter itself,
other co-released neurotransmitters and additional factors. T-cells also produce and secrete some neurotransmitters and may be affected by them in return, by an
autocrine/paracrine mode. Abnormal levels of neurotransmitter receptors in T-cells have been observed in a few
human diseases. If these interesting findings would be
reproduced and extended in future studies, it could mean
that perturbed interactions between neurotransmitters
and T-cells, for example due to too high or low level
of neurotransmitter receptors in T-cells, or due to mal
function of the brain because of chronic stress or injury,
play an active role in the pathogenesis of the respective
diseases, or in the T-cell’s effort to fight the disease.
In conclusion, neurotransmitters may be as important for
the immune system as for the nervous system, and as such
deserve every effort to learn more how they affect T-cells,
where and when. In addition, the direct, rapid, potent,
specific, and receptor-mediated manner by which certain
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470 Immunomodulation
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