Immunologists getting nervous: neuropeptides, dendritic cells and T cell activat

[Guest guest]

Commentary

Immunologists getting nervous: neuropeptides, dendritic cells and T cell

activation

Bart N Lambrecht

Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

Respir Res 2001, 2: 133-138

The electronic version of this article is the complete one and can be found

online at: http://respiratory-research.com/content/2/3/133

Received 20 Feb 2001

Revisions Requested 13 Mar 2001

Revised 21 Mar 2001

Accepted 4 Apr 2001

Published 19 Apr 2001

© 2001 BioMed Central Ltd (Print ISSN 1465-9921 | Online ISSN 1465-993X)

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Keywords: calcitonin gene-related peptide, dendritic cells, substance P, T

cells, vasoactive intestinal peptide

Outline Abstract

Abstract

Introduction

Anatomy of interaction of neuropeptides with the immune system

SP as an immunostimulatory neuropeptide

CGRP, somatostatin and VIP as generally suppressive neuropeptides

Conclusion and suggestions for the future

Note added in proof

Abbreviations

References

It is increasingly recognised that the immune and nervous systems are

closely integrated to optimise defence systems within the lung. In this

commentary, the contribution of various neuropeptides such as substance P,

calcitonin gene-related peptide, vasoactive intestinal peptide and

somatostatin to the regulation of T cell activation is discussed. These

neuropeptides are released not only from nerve endings but also from

inflammatory immune cells such as monocytes, dendritic cells, eosinophils

and mast cells. On release they can exert both direct stimulatory and

inhibitory effects on T cell activation and also indirect effects through

their influence on the recruitment and activation of professional

antigen-presenting dendritic cells. Neuropeptides should therefore be

included in the conceptual framework of the immune regulation of T cell

function by dendritic cells.

Homeostasis within the body is regulated by three interwoven systems: the

endocrine, nervous and immune systems [1]. It is increasingly clear that

exchange of information between these systems is facilitated by the

endocrine and/or paracrine release of hormones, neuromediators and cytokines

by either of these systems and by the shared expression of reciprocal

receptors for these mediators. As an example, T lymphocytes express

neuropeptide receptors for substance P (SP), calcitonin gene-related peptide

(CGRP), somatostatin and vasoactive intestinal peptide (VIP). These

neuropeptides are released from the unmyelinated nerve endings within the

central lymphoid organs and peripheral tissues. At the same time, neural

cells express receptors for cytokines, which are released from the immune

system in a paracrine fashion and affect neural growth and differentiation.

To complicate things further, immune cells themselves can produce

neuropeptides, which influence nervous or immune cells in a paracrine or

autocrine fashion.

In this commentary the pivotal role of neuropeptides in the process of T

cell activation is discussed against the currently prevailing paradigm of T

cell activation by professional antigen-presenting dendritic cells (DCs)

[2]. In this paradigm, the first step in the adaptive immune response of the

T cell is the recognition and uptake of antigen by immature DCs derived from

bone marrow that reside in the periphery of the body and the marginal zone

of the spleen, followed by processing of the antigen into an MHC-associated

peptide that can be recognised by the T cell receptor (TCR).

DCs are professional antigen-presenting cells for three reasons. First, they

express many pattern-recognition receptors for foreign antigen and have the

necessary intracellular enzymes to degrade the antigen into immunogenic

peptides. Second, an encounter with 'dangerous' antigens induces the

functional maturation of DCs and their migration into the T cell area of

draining lymph nodes and spleen, carrying the antigenic cargo into the sites

of T cell recirculation. Third, when mature DCs have reached the draining

lymph node and spleen, they express co-stimulatory molecules such as CD80,

CD86 and intercellular cell-adhesion molecule-1 (ICAM-1) (which are

necessary for optimal T cell activation and the avoidance of T cell anergy),

and produce cytokines such as interleukin (IL)-12 and IL-10 that critically

determine the type of T helper response that is induced [3]. By performing

these three essential functions, DCs are the only antigen-presenting cells

that can induce a primary immune response after transfer into unimmunized

mice, whereas B cells and macrophages fail to do so. Any discussion on the

role of neuropeptides on T cell activation should therefore take into

account not only the direct effects of these mediators on T cells but also

their indirect effects through the modulation of DC function.

Direct interactions between neuropeptides and immune cells are facilitated

by the well-known innervation of both primary (thymus and bone marrow) and

secondary (spleen, lymph nodes, Peyer's patches, tonsils) lymphoid organs by

capsaicin-sensitive nonadrenergic and noncholinergic (NANC) primary afferent

nerve endings and by autonomic nerves containing VIP, somatostatin and

neuropeptide Y [4,5,6]. Within these secondary immune organs, SP and CGRP

containing afferent nerve endings of the NANC system terminate around high

endothelial venules, the sites of specialised extravasation of recirculating

T cells, and in the T cell area and lymphoid follicles, interacting with T

cells, macrophages, mast cells and possibly DCs [6,7]. Outside the immune

system, the direct interaction of nerve endings containing SP and CGRP with

DCs has been described in the skin and in the airway epithelium [8,9].

Within these tissues, the long surface extensions of DCs run parallel to the

extensive network of unmyelinated nerve endings, making interaction very

likely [10].

Although immunohistochemical staining of thymus, spleen and lymph nodes has

demonstrated that neuropeptides such as SP are confined mainly to

unmyelinated nerve endings [11], non-neuronal cells of the immune system can

be a source of tachykinins [5]. Human T lymphocytes contain

preprotachykinin-A mRNA, encoding SP, and produce endogenous SP [12]. Human

and rodent monocytes and macrophages produce SP under baseline conditions

[13,14,15]. More importantly, murine DCs derived from bone marrow were shown

to contain mRNA for the preprotachykinin A gene, and transcription was

confirmed by the demonstration of SP by ELISA and immunohistochemistry [16].

On activation with lipopolysaccharide in vitro there was a marked increase

in SP expression by mononuclear phagocytes and DCs [13,14,16]. The

expression of neuropeptides by these various immune cells could be an

explanation of why not all immunoreactivity for neuropeptides is confined to

nerve endings within secondary immune organs.

During the effector immune response, the process of lymphocyte migration

also allows T cells to migrate into inflammatory lesions within non-lymphoid

organs such as the skin, gut, joint and lung. In these sites, lymphocyte

extravasation is facilitated by neurogenic inflammation and plasma

extravasation that is dependent on the release of SP from

capsaicin-sensitive primary afferent nerve endings via an axon reflex. In a

mouse model of delayed-type hypersensitivity inflammation of the lung

parenchyma, it was shown that SP and VIP were released extensively

(nanomolar concentration range) into the lung parenchyma after challenge

with sheep erythrocytes in sensitised mice, and closely followed the

kinetics of increase in lymphocytes, granulocytes and macrophages in

bronchoalveolar lavage fluid as well as the production of cytokines. During

the induction of inflammation there was an increase in SP immunoreactive

nerve endings within the peribronchial and perivascular leukocytic

infiltrates [17]. Not only are inflammatory areas richly supplied by NANC

neurons, they also contain many inflammatory immune cells, known to produce

neuropeptides (namely macrophages, DCs and lymphocytes). Eosinophils,

extracted from Schistosoma mansoni-induced liver granulomas, have been shown

to produce SP that can influence interferon-ã (IFN-ã) production by

intralesional T lymphocytes [18,19]. The same granulomatous lesions also

contain immunoreactive somatostatin and VIP [20]. Sites of inflammation

within the lung are therefore potentially important areas of interaction

between effector immune cells and locally released neuropeptides.

The NANC nervous system acts through neuropeptide mediators such as the

tachykinins SP, neurokinin A and neurokinin B. There are at least three

distinct tachykinin receptors: neurokinin-1 receptor (NK-1R), NK-2R and

NK-3R, which bind preferentially to SP, neurokinin A and neurokinin B,

respectively [5]. SP is the most widely studied member of the tachykinin

family and modulates a number of important immunological functions, among

which are direct effects on T cell activation. Physiological concentrations

of exogenously added SP (10-11 to 10-13 M) augment antigen- and

mitogen-induced production of IL-2 [21,22] and proliferation in T

lymphocytes in vitro and in vivo [23,24,25]. After administration of SP to

normal and neonatal capsaicin-treated rats, there was an increase in

concanavalin A-induced proliferation of spleen and peripheral blood

lymphocytes, which correlated with an enhanced production of IL-2 and

expression of the IL-2R, CD25, on CD4+ T cells. Moreover, SP markedly

enhanced the percentage of circulating CD25+ CD4+ T cells in the peripheral

blood [26].

Another well-known effect of SP is the stimulation of IFN-ã production by T

cells, an effect that could be due to enhanced IL-12 production by

antigen-presenting cell types [19,27,28]. With few exceptions, the

immunomodulatory effects of SP on lymphocytes can be inhibited by

pharmacological antagonists of NK-1R such as the non-peptide antagonist

SR140333 [22,26]. Moreover, biochemical and molecular evidence has been

obtained that human [12,29,30] and murine lymphocytes [18,31] express NK-1R

but not NK-2R or NK-3R. Human monocytes were also shown to contain NK-1R,

particularly when obtained from lamina propria of mucosal tissues [32]. Lung

and skin DCs also contain binding sites for SP, most probably NK-1R [9].

The demonstration that most immunocytes (monocytes, DCs and lymphocytes)

producing SP also express its receptor led to the hypothesis that SP not

only acts as a mediator of the crosstalk between the nervous and immune

systems but is also biologically involved in the direct interaction between

immune cells in a paracrine and/or autocrine fashion, independently of

sensory nerves or neurogenic inflammation [12,14,16]. Because DCs are highly

involved in the induction and regulation of many immune responses, we have

examined the endogenous expression of SP by DCs and studied its role in the

activation of T lymphocytes. On co-culture of DCs and allogeneic or

syngeneic ovalbumin-specific T cells the addition of a specific NK-1R

antagonist, SR140333, led to a decrease in T lymphocyte proliferation

induced by DCs, an effect that was enhanced when blocking the co-stimulatory

CD80/86-CD28 pathway. These findings were confirmed by the use of responder

T cells derived from NK-1R knockout animals, ruling out any toxic effects of

SR140333 on the observed effects. Moreover, when purified naive NK-1R–/– T

cells were stimulated with stimulatory anti-TCR and anti-CD28 antibodies in

the absence of DCs, there was a decrease in T cell proliferation, revealing

the autocrine release of stimulatory SP by T cells themselves [16]. Indeed,

T cells have been shown to transcribe the mRNA for preprotachykinin A and

release SP on activation with capsaicin [12].

From a number of experiments, direct autocrine and/or paracrine effects of

endogenously released SP on the immunostimulatory capacity of DCs seem less

likely, although it has been shown that SP induces activation of the

transcription factor nuclear factor-êB in murine DCs [9,16,33]. This

transcription factor was previously shown to be pivotal in the upregulation

of stimulatory activity in DCs by upregulating the expression of MHC class

II, the co-stimulatory molecules CD86 and CD80, and levels of IL-12

production [34]. One way in which SP might enhance T cell responses is by

recruiting DCs into sites of damage, when it is released very rapidly from

nerve endings. SP is a chemoattractant for lung-derived DCs in vitro and in

vivo, and in this way it might stimulate the primary immune response by

enhancing immune recognition of dangerous antigens. Moreover, SP is implied

in the recruitment of DCs into sites of inflammation during secondary T cell

responses in the lung and skin, and its depletion leads to severely reduced

delayed hypersensitivity reactions [9]. It is currently unclear how DCs

regulate the release and activity of SP during interaction with T cells, but

one interesting study demonstrated the presence of aminopeptidase N on the

surface of bronchial mucosal L25+ DCs in patients with asthma. This enzyme

has the potential to break down SP [35].

CGRP is released simultaneously with SP from capsaicin-sensitive nerve

endings. In contrast with SP, CGRP directly suppresses IL-2 production and

proliferation in murine T cells [36]. In addition, CGRP-containing nerve

endings are found in close proximity to skin Langerhans cells, and CGRP has

several suppressive effects on DC activation [8,37]. Pretreatment of murine

skin DCs with CGRP led to a decrease in alloresponses in the mixed

lymphocyte reaction, as well as a decrease in ovalbumin-specific T cell

responses of syngeneic T cells [8]. The mechanism by which CGRP mediates its

effects on DCs is slowly being discovered. Signalling via the type I CGRP

receptor expressed on human monocyte-derived DCs and long-lived murine DC

cell lines leads to an increase in intracellular free Ca2+ and to a

decreased expression of MHC class II, the co-stimulatory molecule CD86, and

to a decreased production of IL-12, an effect that could be due to an

enhanced production of IL-10 by these DCs [37,38].

Somatostatin is a widespread neuropeptide with generally inhibitory function

on hormone release in the anterior pituitary and the gastrointestinal system

(for extensive review and references see [39]). In the peripheral nervous

system it is found in sympathetic and sensory neurons innervating the

lymphoid organs, and receptors for somatostatin are located predominantly in

lymphoid follicle germinal centres [6]. Additional non-neuronal sources of

somatostatin (such as granuloma cells within Schistosoma-induced liver

granulomata, lymphocytes, macrophages and thymic DCs) have been described.

The presence of binding sites for somatostatin and the expression of mRNA

for somatostatin receptors (sstr1-5) on lymphocytes and monocytes is

established, although the expression of a particular somatostatin receptor

subtype on T lymphocytes seems to vary with species and with the origins of

the T cells.

Somatostatin is generally inhibitory for T cell proliferation, especially in

the presence of suboptimal stimulatory conditions. Indeed, the

administration of antisense oligodeoxynucleotides designed to block the

translation of somatostatin leads to an enhanced spontaneous proliferation

of rat splenocytes in vitro [40]. In addition, somatostatin suppresses the

production of IFN-ã from murine and human T lymphocytes, a finding that has

deserved the most attention within the granulomatous inflammation induced by

Schistosoma, where it generally antagonises the stimulatory effects of SP

and vice versa [20,27]. Similarly, granulomata of sarcoidosis patients have

been known to bind the somatostatin receptor ligand octreotide in vivo [39].

The precise contribution of somatostatin to the immunostimulatory function

of DCs remains to be determined, although certain DC subsets contain

immunoreactive somatostatin.

VIP and the structurally related pituitary adenylate cyclase-activating

polypeptide (PACAP) are present within immune microenvironments and

inflammatory pulmonary lesions and modulate a number of T lymphocyte

functions ([17]; for review and references see [41]). Macrophages and

lymphocytes themselves produce VIP. Receptors for VIP are located

predominantly at the CD3+ T cell area in lymph nodes and spleen, and include

the VPAC1 receptor (also known as PACAP type II/VIP1) and VPAC2 receptor

(PACAP type III/VIP2) [6]. Although VIP has been known to be a suppressive

neuropeptide for T cell proliferation and production of IL-2, IL-4 and

IL-10, as well as an anti-inflammatory mediator, there are a number of

recent studies suggesting that VIP might have a dual role, also enhancing

certain lymphocyte functions by interacting with different VIP receptors

[42,43]. VIP and PACAP inhibit the activation-induced cell death of

activated T cells by inhibiting the expression of Fas ligand, possibly

leading to a prolongation of immune responses [44]. The stimulatory effects

of VIP on T cell proliferation occurred specifically when stimulated by

antigen-pulsed antigen-presenting cells, suggesting an indirect effect of

VIP. By signalling through the VPAC1 receptor, VIP was shown to induce the

maturation of immature DCs leading to an enhanced production of IL-12 and an

enhanced expression of the DC-maturation marker CD83, especially in the

presence of suboptimal amounts of tumour necrosis factor-á [45].

Many recent studies have illustrated the importance of immune regulation by

neuropeptides through direct effects on T cells and indirect effects on

antigen-presenting DCs (see Fig. 1). The accumulated data also suggest that

neuropeptides are biologically involved in the direct interaction between

immune cells in a paracrine and/or autocrine fashion, independently of

sensory nerves. These studies have largely used in vitro systems in which

concentrations of neuropeptides could be outside the physiological range and

in which no account was taken of the normal anatomical distribution of

lymphocytes and neural innervation of lymphoid organs and peripheral

tissues. Most models that have emerged from these studies have not

integrated the effects of neuropeptides with those of cytokines or mediators

released from inflammatory cells. For example, it is at present unclear

whether and how neuropeptides can modulate such important functions as T

helper cell differentiation, tolerance induction and lymphocyte migration.

Clearly, studies in vivo on the role of neuropeptides will be facilitated by

the use of pharmacological antagonists of neuropeptide receptors and of

knockout mouse strains lacking particular neuropeptides or their receptors

[16,17]. Ultimate proof of the contribution of neuropeptides to human T

cell-mediated diseases awaits the results of clinical interventions with the

newer and highly selective antagonists of the various neuropeptide

receptors.

Using nested PCR and monoclonal antibodies, it was very recently shown that

human and murine DCs express NK-1R (Marriott I, Bost KL: J Neuroimmunol

2001, 114:131–141).

CGRP = calcitonin gene-related peptide; DC = dendritic cell; IFN-ã =

interferon-ã; IL = interleukin; NANC = nonadrenergic and noncholinergic; R =

receptor; SP = substance P; TCR = T cell receptor; VIP = vasoactive

intestinal peptide.

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