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Localization of Receptors for Vasoactive Intestinal Peptide, Somatostatin,
and Substance P in Distinct Compartments of Human Lymphoid Organs
By Jean Claude Reubi, Ursula Horisberger, Andreas Kappeler, and Jean A. Laissue
Regulatory peptides, such as vasoactive intestinal peptide
(VIP), somatostatin (SS), or substance P (SP), are considered
to play a role in immune regulation. To localize the targets of
these peptides in the human immune system, their receptors
have been evaluated with in vitro receptor autoradiography
in lymph nodes, tonsils, appendix, Peyer’s patches, spleen,
and thymus. The three peptide receptors were detected in all
lymphoid tissues tested, but, unexpectedly, usually in distinct compartments. In lymph nodes, palatine tonsils, vermiform appendix, and Peyer’s patches, VIP receptors were
found in the CD3 positive zone around lymphoid follicles; SS
receptors in the germinal centers of secondary follicles; and
SP receptors mainly in interfollicular blood vessels. In the
spleen, VIP receptors were detected in periarterial lymphatic
sheaths, SS receptors in the red pulp, and SP receptors in the
central arteries. In the thymus, VIP receptors were present in
cortex and medulla, SS receptors in the medulla, and SP
receptors in blood vessels. For comparison, cholecystokinin
(CCK)-A and -B receptors were not demonstrated in any of
these tissues. These results suggest a strong compartmentalization of the three peptide receptors in human lymphoid
tissues and represent the molecular basis for the understanding of a very complex and interactive mode of action of these
peptides.
r 1998 by The American Society of Hematology.
R
Table 1. Type and Number of Human Lymphoid Tissues Investigated
and Their Peptide Receptor Status
EGULATORY PEPTIDES, in particular gut and brain
peptides, have been shown to be involved in the regulation of immune processes in numerous animal and human
studies.1-3 First, receptors for various regulatory peptides, ie,
somatostatin (SS), vasoactive intestinal peptide (VIP), or substance P (SP) are expressed by rat, mice, or human immunocytes, in particular lymphocytes.1,4-12 Second, various effects of
these regulatory peptides have been reported in vivo or in vitro
on several immunologic parameters: SS has been shown to
inhibit murine lymphocyte proliferation,13-15 Ig synthesis,13,16,17
or the release of colony-stimulating factor18 and to enhance the
formation of leukocyte-migration inhibiting factor in activated
lymphocytes.13 VIP regulates immunocompetence in vitro including antibody production, natural killer activity, histamine
production by mast cells, and lymphocyte proliferation.2,3
Effects of SP on immunocompetence have also been documented19 and are probably exerted through the carboxyterminal domain of the 11-amino acid neuropeptide.9
Moreover, several investigations have described interactions
between several regulatory peptides involved in immune functions, suggesting close topographical links between the various
peptide systems.2,20-25 For instance, in murine Peyer’s patch
cells, mesenteric lymph node cells and splenocytes, SS and VIP
reduce cell proliferation driven by a T-cell lectin, whereas SP
increases it. SS can antagonize the SP- or VIP-induced stimulation of immunoglobulin production.1,25 SS and VIP can increase
the cholecystokinin (CCK)-induced inhibition of Molt-4 lymphoblast proliferation.21
Much progress has been made recently in the molecular
characterization of the receptors for SS, VIP, SP, and CCK at the
protein and mRNA levels, in particular with the identification of
the existence of several subtypes for each of these receptors.26-29
Despite these data, little is known about the cellular localization of receptors for peptides and about regulatory interactions
of peptides in human lymphoid tissues. Therefore, we have
investigated the tissue localization of various regulatory peptide
receptors, including SS receptors, VIP receptors, SP receptors,
CCK-A receptors and CCK-B receptors, using in vitro receptor
autoradiography in human thymus, lymph nodes, spleen, tonsils, appendix, and Peyer’s patches.
Blood, Vol 92, No 1 (July 1), 1998: pp 191-197
Presence of Regulatory Peptide Receptors
Tissue
VIP-R
SS-R
SP-R
CCK-A-R
CCK-B-R
Lymph nodes
Tonsils
Appendix
Peyer’s patches
Spleen
Thymus
27/27
8/8
11/11
9/9
6/6
9/9
27/27
8/8
11/11
9/9
6/6
9/9
9/9
8/8
5/5
9/9
6/6
9/9
0/7
0/3
0/4
0/2
0/4
0/4
0/7
0/3
0/4
0/2
0/4
0/4
MATERIALS AND METHODS
Aliquots of surgically resected tissues or of biopsies submitted for
diagnostic histopathology were frozen immediately after surgical
resection and stored at 270°C. The specimens originated primarily
from the Institute of Pathology, University of Berne, Berne, Switzerland. The various nondiseased lymphoid tissue samples investigated
included thymus, lymph nodes, spleen, tonsils, appendix, and Peyer’s
patches. Each tissue was cut in 10- or 20-µm thick, successive sections
on a cryostat. Alternate sections were used for in vitro receptor
autoradiography (20 µm) for VIP receptors, SS receptors, SP receptors,
or CCK-A and CCK-B receptors, and for immunohistochemical staining (10 µm) for various antigens (CD3, MIB-1, DRC-1, F-VIII) known
to be present in lymphoid tissues.
VIP receptor autoradiography. [125I]-labeled VIP (2,000 Ci/mmol;
Anawa, Wangen, Switzerland) was used as the radioligand. Only the
mono 125Iodo-[Tyr10]-VIP, eluted as single peak from the high-
From the Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland.
Submitted October 6, 1997; accepted February 14, 1998.
Address reprint requests to Jean Claude Reubi, MD, Professor of
Pathology, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31,
CH-3010 Berne, Switzerland.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
this fact.
r 1998 by The American Society of Hematology.
0006-4971/98/9201-0028$3.00/0
191
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REUBI ET AL
Fig 1. Localization of VIP receptors, SS receptors,
and SP receptors in the various compartments of a
human appendix. Successive sections were used. (A)
Autoradiogram showing total binding of 125I-VIP.
Predominant VIP receptor-location is in the zone
surrounding lymphoid follicles. (B) CD3 immunohistochemical staining. (C) Hematoxylin-eosin stained
section. Bar 5 1 mm. (D) Blood vessels stained for
F-VIII related antigen. (E) Autoradiogram showing
total binding of 125I-Tyr3-octreotide. Predominant SS
receptor location is in the germinal centers. (F) DRC-1
immunohistochemical staining for reticulum cells.
(G) MIB-1 immunohistochemical staining for proliferating cells. (H) Autoradiogram showing total binding
of 125I-BH-SP. Predominant SP receptor location is in
the blood vessels, but not in lymphoid tissue.
performance liquid chromatography (HPLC) and analyzed by mass
spectrometry, was used. The slide-mounted tissue sections were incubated for 90 minutes in a solution of 50 mmol/L Tris-HCl (pH 7.4)
containing 2% bovine serum albumin (BSA), 2 mmol/L EGTA, 0.1
mmol/L bacitracin, and 5 mmol/L MgCl2 to inhibit endogeneous
proteases in the presence of 30 pmol/L [125I]-labeled VIP at room
temperature as described previously.30 To estimate nonspecific binding,
paired serial sections were incubated as described above, except that 1
µmol/L VIP (Bachem, Bubendorf, Switzerland) was added to the
incubation medium. After this incubation, the slides were washed twice
in ice-cold 50 mmol/L Tris-HCl (pH 7.4) containing 0.25% BSA, then
in buffer alone, and quickly dried under a stream of cold air. The
sections were subsequently exposed to a 3H-Hyperfilm (Amersham,
Little Chalfont, UK) for 1 week.
Selected VIP receptor-positive lymphoid tissues were evaluated with
125I-[Ac-His1]pituitary adenylate cyclase activating peptide (PACAP)
1-27 for their receptor subtype specificity: displacement experiments
under the same conditions as for VIP receptor autoradiography using
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PEPTIDE RECEPTORS IN HUMAN LYMPHOID ORGANS
193
increasing concentrations of unlabeled VIP and PACAP 1-27 were
performed to differentiate PACAP-I and PACAP-II receptors.31
SS receptor autoradiography. The radioligands used were 125Ilabeled [Tyr3]-octreotide and 125I-[Leu8,D-Trp22,Tyr25]-SS-28 (125I[LTT]-SS-28) known to specifically label SS receptors. Both ligands
were iodinated, purified by high pressure liquid chromatography
column, and characterized in standard binding assays as described
previously.4,32 Frozen sections were then incubated for 2 hours at
ambient temperature in the presence of 65 pmol/L 125I-[Tyr3]-octreotide.
The incubation solution was 170 mmol/L Tris-HCl buffer (pH 8.2)
containing 1% BSA, bacitracin (40 µg/mL), and MgCl2 (10 mmol/L) to
inhibit endogenous proteases. Nonspecific binding was determined by
adding 1 µmol/L solution of unlabeled [Tyr3]-octreotide or SS-28.
Incubated sections were washed twice for 5 minutes in cold incubation
buffer containing 0.25% BSA and then in buffer alone and dried quickly.
Finally, the sections were apposed to 3H-Hyperfilms (Amersham, Little
Chalfont, UK) and exposed for 1 week in x-ray cassettes.
Adjacent sections from some of the tissues tested with 125I-labeled
[Tyr3]-octreotide were also examined for specific binding with the
SS-28 radioligand 125I-[LTT]-SS-28 to evaluate whether the same tissue
elements were identified by both ligands.
SP receptor autoradiography. The radioligand used was 125I-BoltonHunter–SP (125I-BHSP) (2,000 Ci/mmol; Anawa) as described.33 The
sections were incubated for 2 hours in a solution of 50 mmol/L Tris-HCl
(pH 7.4) containing BSA (0.02%), chymostatin (2 mg/L), leupeptin (4
mg/L), bacitracin (40 mg/L), MnCl2 (5 mmol/L), and 50 pmol/L
125I-BHSP at room temperature. To estimate nonspecific binding, paired
serial sections were incubated as described above, except that 1 µmol/L
SP (Bachem) was added to the incubation medium. After this incubation, the slides were rinsed with four washes of 30 seconds each in
ice-cold 50 mmol/L Tris-HCl (pH 7.4), dipped in ice-cold distilled
water, and then quickly dried in a refrigerator under a stream of cold air.
The sections were subsequently exposed to a 3H-Hyperfilm (Amersham) for 1 week.
CCK receptor autoradiography. Lymphoid tissues underwent receptor autoradiographic processing with two different radioligands: 125ILeu15-gastrin-I(125I-gastrin) or 125I-D-Tyr-Gly-Asp-Tyr(SO3H)-Nle-GlyTrp-Nle-Asp-Phe-amide (125I-CCK), as described in detail previously,34,35
for the identification of CCK-A and CCK-B receptors.
Immunohistochemistry. Immunostaining for CD3 (clone UCHT1;
Dako, Glostrup, Denmark), follicular dendritic cells (clone R4/23;
Dako), factor VIII-related antigen (clone F8/86; Dako), and proliferation antigen Ki-67 (clone MIB-1; Immunotech, Marseille, France) was
performed on sections adjacent to those used for receptor autoradiography. Cryostat sections (5 µm) were fixed in acetone, air-dried, rehydrated in 5% rabbit serum, and then sequentially incubated with a
primary antibody, a biotinylated rabbit antimouse immunoglobulin
antibody (Dako), and a complex of avidin and biotinylated alkaline
phosphatase (Dako), according to the avidin-biotin-complex (ABC)technique. Finally, slides were developed in new fuchsin and mounted
without counterstaining. In negative controls, the primary antibody was
replaced with an irrelevant mouse monoclonal antibody.
RESULTS
As shown in Table 1, three peptide receptors were found to be
consistently expressed in human lymphoid tissues, namely VIP
receptors, SS receptors, and SP receptors, whereas CCK-A and
CCK-B receptors were not identified. The most interesting
finding is that in the lymph nodes, appendix, and Peyer’s
patches, VIP receptors, SS receptors, and SP receptors were
localized in different, complementary tissue compartments:
whereas SS receptors were found in the germinal centers of
lymphoid follicles, VIP receptors were predominantly localized
in the zone around the follicles and SP receptors in blood
Fig 2. Localization of VIP receptors, SS receptors, and SP receptors in successive sections of a human Peyer’s patch. (A) CD3
immunohistochemical staining. Bar 5 1 mm. (B) Autoradiogram
showing total binding of 125I-VIP. Arrows point towards VIP receptors
located in the peripheral zone of the lymphoid follicle. (C) Autoradiogram showing total binding of 125I-Tyr3-octreotide. Arrowhead shows
SS receptors in the germinal center. (D) Autoradiogram showing total
binding of 125I-BH-SP. SP receptors are located in the blood vessels.
vessels located in this zone (Figs 1 through 3). In the thymus, a
low density of VIP receptors was distributed in medulla and
cortex, whereas SS receptors were mainly expressed in the
epithelial cells of the medulla and SP receptors were found in
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194
REUBI ET AL
the thymic vessels (Fig 4). In the spleen, the VIP receptors were
located in the periarterial lymphatic sheets (Fig 5), whereas SS
receptors were found diffusely in the red pulp and SP receptors
in the central arteries of the white pulp (Fig 5).
The tissue localization of the receptors was compared with
that of lymphocyte subpopulations in defined tissue areas in
lymphoid organs: in the lymph nodes, appendix, Peyer’s
patches, tonsils, and thymus, the VIP receptor localization
correlated best with that of CD3 immunoreactivity (Figs 1
through 4), that is, it was located in T-lymphocyte areas.
Conversely, SS receptor localization correlated best with that of
germinal centers of lymphatic tissue, as indicated by the
reactivity of the latter for DRC-1 and MIB-1, eg, in the
appendix in Fig 1. SP receptors were primarily located in
vessels (Fig 1), in particular, high endothelial venules and in
vascular sinuses of the spleen, as shown by the endothelial
reactivity for F-VIII related antigen.
The receptor subtypes expressed by the lymphoid tissues are
likely to be the following: sst2 is the main somatostatin receptor
subtype found in the germinal centers, as in all cases the
sst2-preferring radioligand 125I-Tyr3-octreotide was the ligand
of choice compared with the universal ligand 125I-LTT-SS-28,
which gave a slightly less intense labeling of the same tissue
elements (data not shown). The VIP receptors in T-cell areas are
considered to belong to the PACAP-II receptor subtypes, as in
displacement experiments, VIP and PACAP displaced 125I-VIP
with high affinity; moreover, when 125I-[Ac-His-1]-PACAP
1-27 was used as ligand, both PACAP and VIP displaced the
ligand with high affinity (Fig 6). NK1 appears to be the SP
receptor subtype expressed in the vessels of human lymphoid
tissue, as NK1 selective analogs, but not NK2 or NK3 selective
analogs, displaced 125I-BH-SP with high affinity (data not
shown).
DISCUSSION
Foreign antigens are transported to and concentrated in
peripheral (secondary) lymphoid organs and tissues, including
the spleen, lymph nodes, and mucosa-associated tissues. The
peripheral organs provide an environment in which mature T
and B lymphocytes can interact with each other, with accessory
cells, and with antigens to generate cellular and humoral
immune responses, whereas central lymphoid organs are major
sites of lymphopoiesis. The structural organization of the
various cell populations in the lymph nodes is considered to be
critical for the generation of immune responses.36 This study
represents the first evidence for a striking and unexpected
compartmentalization for three peptide receptors present in
lymphoid organs. The results indicate and confirm that several
regulatory peptide receptors are strongly expressed in central
and peripheral human lymphoid organs and thus may participate in immunoregulatory functions.2,3,25 It is the first time that
the precise tissue distribution of VIP receptors is reported in
human lymphoid organs, as they were consistently and predomi-
;
Fig 3. Complementary localization of VIP receptors and SS receptors in a human lymph node. (A) CD3 immunohistochemical staining.
Bar 5 1 mm. (B) Autoradiogram showing total binding of 125I-VIP. VIP
receptors are in the whole lymph node with exception of the germinal
centers. (C) Autoradiogram showing total binding of 125I-Tyr3octreotide. SS receptors are predominantly located in germinal centers.
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PEPTIDE RECEPTORS IN HUMAN LYMPHOID ORGANS
Fig 4. Localization of VIP receptors, SS receptors, and SP receptors in a human thymus. (A) Hematoxylin-eosin stained section. Bar 5
1 mm. (B) Autoradiogram showing total binding of 125I-VIP. VIP
receptors are diffusely distributed in cortex and medulla. (C) Autoradiogram showing total binding of 125I-Tyr3-octreotide. SS receptors
are located in the medulla. (D) Autoradiogram showing total binding
of 125I-BH-SP. SP receptors are located in blood vessels.
nantly expressed in regions rich in CD3 immunostained cells,
ie, rich in T lymphocytes. These VIP receptor-expressing cells
are quite different from the SS receptor-expressing cells in
secondary follicles, immunoreactive for MIB-1 and DRC-1.
195
Further, the SP receptor-expressing structures were identified as
blood vessels. Thus, all three receptors, VIP receptors, SS
receptors, and SP receptors, are expressed by human lymphoid
organs in different, topographically distinct structures. The
CCK receptors do not appear to play a major role in the tissues
tested in this study.
In lymph nodes, the localization of SS receptors correlated
well with that of germinal centers, defined by the presence of
dendritic and proliferating cells, and suggests their functional
involvement in the regulation of humoral antibody responses.
The adjacent paracortex, containing mostly T lymphocytes of
the helper phenotype, displayed a marked expression for VIP
receptors. Dendritic cells located in T-cell–rich areas are known
to present antigens circulating in the lymph to CD41 helper T
cells. Further, B lymphocytes from the blood must traverse
helper T-cell–rich and VIP receptor-rich zones on their way to
the follicles, hence maximizing the chance for cellular interactions. Because lymphocytes enter and egress via lymphatics and
high endothelial venules, the presence of SP receptors in blood
vessels may play a regulatory role for lymphocyte traffic and
recirculation. Thus, the anatomic organization of lymph nodes
provides multiple sites for cellular interactions. The compartmentalized distribution of receptors for small peptide hormones in
the lymph nodes reflects, to a certain extent, the structural, and
probably functional, organization of the various cell populations in the lymph nodes.
In the tonsils, Peyer’s patches and vermiform appendix,
which are part of the mucosa-associated lymphoid system, the
distribution of receptors for peptides was comparable to that
noted in lymph nodes. The secondary follicles displayed SS
receptors, perifollicular areas VIP receptors, and vessels, SP
receptors. The epithelium overlying mucosal lymphoid tissues
are known to allow the transport of antigens. Mucosa-associated
cells mainly recirculate within the mucosal lymphoid system.
In the spleen, which responds mainly to blood-borne antigens, the bulk of the lymphoid tissue, arranged around a central
SP receptor-positive arteriole in the white pulp, constitutes the
periarteriolar lymphoid sheath that contains mainly T lymphocytes and that also displayed VIP receptors. The primary or
secondary follicles with a germinal center, attached to the
periarteriolar sheath, have the same anatomic features and
functions as in lymph nodes, and also display SS receptors. The
red pulp contains resident leukocytes and diffusely distributed
SS receptors. The venous sinuses in the red pulp bear SP
receptors; blood cells can reenter the circulation by crossing the
highly discontinuous walls of these sinuses.
In the human thymus, cortex and medulla display a low
density of VIP receptors that seems to be associated with T
cells. A network of epithelial cells in the lobules, expressing SS
receptors in the medulla, plays a role in the thymocytic
differentiation process. Cell traffic occurs via high endothelial,
SP receptor-positive venules near the corticomedullary junction.
The observed distribution pattern of the respective peptide
receptors is compatible with data reported in previous studies
obtained by other methods, eg, by the use of isolated cells. For
instance, the present findings of a predominant VIP receptor
expression in T lymphocytes is compatible with several reports
showing that VIP receptors are present in lymphocyte-rich
fractions; these T cells have a much higher binding capacity for
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196
REUBI ET AL
identified in the immediate vicinity of lymphoid organs.40 The
localization of these VIP fibers correlate with that of VIP
receptors detected in the present study. These findings probably
represent the basis for the proposed neuroimmune interactions.2,3 The peripheral nervous system is also likely to be the
source for SS acting on germinal centers40 or SP acting on blood
vessels.
It is presumably not yet possible, on the basis of these
receptor data, to present a unifying concept of the specific
actions of these peptides in human lymphoid tissues, as well as
their specific interactions, and to bring them together with those
proposed from in vivo experiments in animals and humans.
Indeed, when interpreting the numerous in vivo studies involving regulatory peptides, we have to be aware of the fact that this
class of substances is characterized by multiple actions in man:
in addition to immunomodulatory actions, several endocrine,
neural, gastrointestinal, vascular, and other actions have been
Fig 5. Localization of VIP receptors and SP receptors in the human
spleen. (A) CD3 immunohistochemical staining of the periarterial
lymphatic sheaths (arrows). Bar 5 1 mm. (B) Autoradiogram showing
total binding of 125I-VIP. Preferential labeling is seen in the periarterial
lymphatic sheets (arrows). Nonspecific binding is negligible. (C)
Hematoxylin-eosin staining showing several central arteries (arrowheads) Bar 5 1 mm. (D) Autoradiogram showing total binding of
125I-BH-SP. Only the central arteries are labeled. Nonspecific binding is
negligible.
VIP than non-T cells, and the proportion of these cells in lymph
nodes, spleen, and Peyer’s patches is higher than in thymus.6,7,37
SS receptors were shown earlier by us to be predominantly
expressed by the germinal centers of lymph nodes, tonsils, and
Peyer’s patches, as well as by the red pulp of the spleen and the
medulla of the thymus.4,38 Further, SP receptors were identified
previously by us33 and by Tang et al39 in the vascular compartments of lymphoid organs, ie, high endothelial venules and
vascular sinuses, rather than in lymphoid cells. Our present
results are in agreement with these observations and show, in
addition, the presence of SP receptors in the splenic central
arteries.
Endogenously synthesized regulatory peptides are likely to
be present in sufficient amounts in the immediate vicinity of the
reported receptor-expressing targets. Among all the potential
sources of VIP, it appears that VIP originating from peripheral
nerve endings is the most likely to act on VIP receptorcontaining lymphoid cells, as dense VIP-containing fibers were
Fig 6. Displacement curves of 125I-[Ac-His-1]-PACAP(1-27) to tissue
sections of a human thymus (A) and a human lymph node (B). Tissue
sections are incubated with 15,000 cpm/100 mL radioligand and
increasing concentrations of PACAP(1-27) (m) and VIP (j), or somatostatin (SS-14) (d) at a concentration of 100 nmol/L. Nonspecific
binding was subtracted from all values. In all cases, complete
displacement of the ligand is achieved by VIP and PACAP. SS-14 was
inactive in the nanomolar range.
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PEPTIDE RECEPTORS IN HUMAN LYMPHOID ORGANS
described. In vivo effects of these peptides on immune function
may therefore result from indirect effects on secretory cells,
nerve cells, or cells of the vascular apparatus. Influences of
peptides in vivo on immune functions may also vary with the
presence of other signal molecules (ie, other peptides) with the
resident cell population in the lymphoid tissue and with the actual
microenvironment. The present study has primarily pointed towards
a number of specific structures of the lymphoid system where these
regulatory peptides may play a predominant role.
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From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1998 92: 191-197
Localization of Receptors for Vasoactive Intestinal Peptide, Somatostatin,
and Substance P in Distinct Compartments of Human Lymphoid Organs
Jean Claude Reubi, Ursula Horisberger, Andreas Kappeler and Jean A. Laissue
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