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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 207-214
Adhesion, Transendothelial Migration, and Reverse Transmigration
of In Vitro Cultured Dendritic Cells
By
Giovanna D'Amico,
Giancarlo Bianchi,
Sergio Bernasconi,
Laura Bersani,
Lorenzo Piemonti,
Silvano Sozzani,
Alberto Mantovani, and
Paola Allavena
From the Department of Immunology and Cell Biology, "Mario
Negri" Institute, Milan; and the Section of General Pathology,
University of Brescia, Brescia, Italy.
 |
ABSTRACT |
Dendritic cells (DC) are migratory cells which exhibit complex
trafficking properties in vivo, involving interaction with vascular and
lymphatic endothelium and extracellular matrix (ECM). The underlying
mechanisms involved in these processes are still ill defined. In the
present study we have investigated the ability of DC to interact in
vitro with human vascular endothelial cells (EC) and ECM. DC were
differentiated from monocytes by in vitro exposure to
granulocyte-macrophage colony-stimulating factor and interleukin-13 for
7 days. In adhesion assays a considerable proportion of DC bound to
resting EC monolayers: (17% ± 4%, mean ± SE of eight
experiments). Adhesion to tumor necrosis factor (TNF)-activated EC was
increased to 29% ± 5% (n = 8). Binding to resting EC was strongly inhibited by anti-CD11a and CD11b, but not by CD11c monoclonal antibodies (MoAbs); on TNF-activated EC, anti-VLA-4 in concert with
anti-CD18 inhibited adhesion by more than 70%. Binding to a natural
ECM, derived from cultured EC, or to purified fibronectin was high:
52% ± 6% (n = 8) involved VLA-4 and VLA-5
integrins. In a transmigration assay, 10% ± 2% (n = 6) of input
cells were able to cross the EC monolayer. Unlike adhesion,
transendothelial migration was significantly reduced by anti-CD31 MoAb.
The amount of DC transmigrated through a monolayer of EC was increased
twofold to threefold by a defined set of C-C chemokines including
RANTES, MIP1 , MIP5, and, to a lesser extent, by MIP1
and MCP-3. Most importantly, in view of the trafficking pattern of
these cells, a significant proportion of DC (13% ± 4% of input
cells seeded) was able to migrate across the endothelial basement
membrane and, subsequently, across the endothelial barrier (reverse
transmigration). The adhesion molecules and chemoattractants
characterized herein are likely to underlie the complex trafficking of
DC in vivo.
| |
INTRODUCTION |
DENDRITIC CELLS (DC) are bone marrow
(BM)-derived leukocytes specialized in antigen capture, processing, and
presentation to T lymphocytes. DC are most potent among
antigen-presenting cells (APC) and are believed to be indispensable to
initiate a primary immune response.1-5 DC progenitors from
the BM enter the blood and seed nonlymphoid tissues. Immature DC are
localized in epithelia, such as skin epidermis (Langherans cells),
gastrointestinal and genito-urinary tract, airways, and the
interstitial space of many solid organs (heart, liver,
kidney).1,6
Upon the encounter of an antigen, DC migrate from the site of residence
to the T-cell areas of regional lymph nodes. These migratory cells also
undergo maturation from a "processing" to a "presenting"
stage, characterized by the loss of antigen uptake and by an increased
capacity to stimulate T cells.1-5 Locally produced
inflammatory cytokines (eg, tumor necrosis factor [TNF] and
interleukin-1 [IL-1]) and bacterial products can stimulate the
maturation and migration of DC from resident tissues to lymph nodes.6-11
Some pathways of DC migration in vivo and recruitment of DC precursors
from blood to tissues have been characterized. TNF and possibly other
lipopolysaccharide (LPS)-derived cytokines quickly recruited DC in the
airway epithelia in a model of respiratory infection.8
Intradermal administration of granulocyte-macrophage colony-stimulating
factor (GM-CSF) lead to an increase in the number of DC within the
human dermis.12 After intravenous injection of inert
particles, phagocytic cells are recruited to the hepatic sinusoid and
these cells then translocate to the hepatic lymph.13 After
intratracheal injection of an antigen, antigen-loaded DC are found in
the draining lymph nodes.14 Systemic administration of LPS
also induced a profound loss of major histocompatibility complex (MHC)
class II+ cells from mouse heart and kidney, probably
because of migration.10,11
Large quantities of cells with the typical features of DC can be easily
differentiated in vitro from CD34+ stem cells upon culture
with GM-CSF and TNF,15,16 or from monocytes with GM-CSF and
IL-4.17-19 We recently showed that IL-4 can be fully
substituted by IL-13.20
Although some pathways of DC migration have been identified, the
molecular mechanisms regulating their tissue trafficking are not fully
elucidated. We and others have characterized the capacity of in vitro
cultured DC to respond to chemotactic signals, including classical
peptides (eg, C5a) and lipid (eg, platelet-activating factor [PAF])
agonists as well as chemokines.21-25 DC respond to a unique
spectrum of chemokines which overlaps but is distinct from that active
on other leukocytes, which includes the CC molecules MCP-3, Rantes,
MIP1, MIP1, MCP-4, HCC2/MIP5, and the C-X-C chemokine SDF-1.22,26 Moreover, the recently identified chemokine
macrophage-derived chemokine (MDC) is 100 times more
active on DC than on monocytes.27 There is heterogeneity
among DC in chemokine responsiveness as illustrated by the observation
that CD34-derived, but not monocyte-derived, DC express CCR6 and,
accordingly, respond to MIP3.28,29 The chemotactic
response to chemokines suggest that these molecules may have a role in
regulating the trafficking of DC in vivo.
During migration from the tissue of residence to afferent lymphatics,
DC interact with extracellular matrix (ECM) and with the endothelial
lining of lymphatic vessels. DC interact also with blood endothelial
cells (EC) during recruitment of precursors from the blood into tissues
and during migration to spleen.6
No information is available on the ability of DC to adhere and to
transmigrate through vascular EC. In the present study we have
addressed the question of how DC interact with EC and ECM in vitro,
which adhesion molecules are engaged, and which chemotactic signals
direct their transendothelial migration. Moreover, we devised a simple
methodological approach to investigate the capacity of DC to enter
vessels from tissues, which we named reverse transmigration.
| |
MATERIALS AND METHODS |
Culture media and reagents.
The following reagents were used for separation of effector cells, cell
culture, and experimental assays: pyrogen-free saline for clinical use
and distilled water (Bieffe, Sondrio, Italy); medium RPMI 1640 (10×
concentrated; Biochrom KG, Berlin, Germany); medium 199 (GIBCO,
Paisley, UK); glutamine (GIBCO); penicillin and streptomycin (GIBCO);
aseptically collected fetal calf serum (FCS; Hyclone, Logan, UT). The
routinely used tissue culture medium was RPMI 1640 with 2 mmol/L
glutamine, 50 µg/mL of gentamicin, 10% FCS.
Cytokines.
Human recombinant GM-CSF was from Sandoz (Basel, Switzerland). Human
recombinant (r) TNF- was from BASF (Knoll, Germany). Human rIL-13
and MCP-3 were from Sanofi Elf Bio Recherches (Labège, France).
Human rMIP-1 was from PeproTech Inc (Rocky Hill, NJ). Human
rMIP-1 was from Dr L. Czaplewski (British Biotechnology Limited,
Cowley, UK). RANTES and MIP-5/HCC2 were chemically
synthesized.30 MIP-5/HCC2 is a novel human CC chemokine
that shows high sequence identity to MIP-3 (76.7%), MIP-4 (63.2%),
MIP-1 (75.4%), and MIP-1 (66.7%).26 Cytokines were
endotoxin free as assessed by Limulus Amebocyte assay
(BioWhittaker, Walkersville, MD).
DC culture.
DC were differentiated in vitro as previously
described.20,22,26,31 Highly enriched blood monocytes
(>95% CD14+) were obtained from buffy coats (through
the courtesy of Centro Trasfusionale, Ospedale Sacco, Milan, Italy) by
Ficoll and Percoll gradients and purified by panning on CD6-coated
plastic dishes. Monocytes were cultured for 7 days at 1 × 106/mL in 6-well Multiwell tissue culture plates (Falcon,
Becton Dickinson, Lincoln Park, NJ) in RPMI 1640 + 10%
FCS supplemented with 50 ng/mL GM-CSF and 10 ng/mL IL-13.
In a limited number of experiments, DC were differentiated from
CD34+ cells purified from human cord blood and cultured for
14 days in the presence of stem cell factor (50 ng/mL), GM-CSF (50 ng/mL), and TNF (10 ng/mL).
Mixed leukocyte reaction.
Cultured DC were irradiated (3,000 rad) and added in graded doses to 1 × 105 purified allogeneic T cell in 96-well
round-bottomed microtest plates. Responder cells were depleted of
autologous APC by passage with CD14- and CD19-coated Dynabeads
(Unypath, Milan, Italy). Each group was performed in triplicate.
3H-thymidine incorporation was measured on day 5 by 16-hour
pulse (5 Ci/µmol; Amersham, Amersham, UK).
Monoclonal antibodies (MoAbs).
The following MoAbs were used: L243 (IgG2a, anti-MHC class II)
purchased from American Type Culture Collection (ATCC; Rockville, MD);
NA1/34 (IgG2a, anti-CD1a; Dako, Glostrup, Denmark); UCHM1 (IgG2a, anti-CD14; a kind gift from Dr P. Beverly, London, UK); TS1/22
(IgG1, anti-CD11a) and TS1/18 (IgG1, anti-CD18) from ATCC; 44a (IgG2a,
anti-CD11b; a kind gift from Dr R. Todd, Ann Arbor, MI); L29 (IgG1
anti-CD11c; a kind gift from Dr L. Lanier, DNAX Palo Alto, CA); HP2/1
(IgG1 anti-VLA4; a kind gift from Dr. F. Sanchez-Madrid, University of
Madrid, Madrid, Spain); M89D3 [an F(ab )2 fragment of
anti CD31; a kind gift from Dr R. Zocchi, Ist. S. Raffaele, Milan, Italy]; SK11 (IgG2a anti-CD62L) and RUU-PL (IgG1
anti-CD61) were from Becton Dickinson (Mountain View, CA).
In adhesion or transmigration assays, optimally diluted MoAbs were
preincubated with the cells for 20 minutes before plating; medium
control contained an isotype-matched irrelevant MoAb. For fluorescence-activated cell sorter (FACS) analysis, cell staining with
primary MoAb was followed by fluorescein isothiocyanate
(FITC)-conjugated affinity purified, isotype-specific goat anti-mouse
antibodies (Valter Occhiena, Torino, Italy). Results are
expressed as percent of positive cells and as relative fluorescence
intensity (RFI), calculated according to the formula: RFI = Mean
Fluorescence (sample)  Mean Fluorescence (control)/Mean Fluorescence
(control).
Preparation of EC.
Human EC were obtained from umbilical vein (HUVEC) and cultured as
previously described.32 Routinely we used confluent cells (105/2-cm2 culture well) between the first and
fourth passage maintained in 199 medium with 20% bovine serum
(Hyclone) supplemented with endothelial cell growth supplement (50 µg/mL; Collaborative Research Inc, Lexington, MA) and heparin (100 µg/mL; Sigma Chemical Co, St Louis, MO). The purity of EC cultures
was checked by expression of von Willebrand factor and found to be
greater than 99% positive.
Adhesion assay.
Adhesion of DC to EC was studied as described previously.33
EC were grown to confluence in flat-bottomed 48-well trays. 51Cr-labeled DC (Amersham, UK) were coincubated with EC
monolayers at 37°C for 1 hour. At the end nonadherent cells were
washed away and adherent cells were solubilized with 0.1 mL of 0.1%
sodium dodecyl sulfate and radioactivity was counted in a gamma
counter. Results represent the percent of adherent cells ± SD of
three replicates/group.
Transmigration and reverse transmigration assay.
This assay was performed as previously described.34 In
brief, EC were grown to confluence on polyvinylpyrrolidone
(PVP)-free polycarbonate filters (5-µm pore) and
mounted on modified Boyden chambers over a nitrocellulose filter.
51Cr-labeled DC were seeded in the upper compartment and
coincubated with EC monolayers for 1 hour at 37°C. Nonadherent cells
were gently washed away, the radioactivity in the double
filter and in the lower compartment referred to transmigrated cells.
The adherent cells were considered to comprise both cells bound to EC
as well as those that had transmigrated.
In the reverse transmigration assay an upper polycarbonate filter was
coated with ECM, and the lower polycarbonate filter was coated by a
monolayer of EC, placed upside down, and mounted in the Boyden chamber.
The ECM was prepared by growing a monolayer of EC on filters for at
least 5 days; EC were then stripped away by a short treatment with a 20 mmol/L NH4OH solution + 0.5% Triton X-100
(Sigma, St Louis, MO) for 30 seconds. In this assay the radioactivity
present in the lower compartment only accounted for the transmigrated
cells.
In some experiments polycarbonate transwell inserts (5-µm pore;
Corning, Costar, Cambridge, MA) were used. Inserts were coated with EC
monolayers; chemoattractants, usually 100 ng/mL, were seeded in the
lower compartment.
| |
RESULTS |
In vitro adhesion of DC to EC monolayers and ECM.
DC were differentiated in vitro from highly purified human monocytes in
the presence of GM-CSF + IL-13 for 7 days. As previously reported these
cultured DC expressed high levels of CD1a and MHC class
II and had low levels of CD14. As APC, they were strong stimulators of allogeneic T-lymphocyte proliferation in
MLR.20,26
In preliminary experiments we evaluated the role of IL-13 on the
adhesive ability of cultured DC. There was a concern in performing adhesion assays with cells cultured in the presence of IL-13, as we
reported that IL-4, a functionally related cytokine, strongly inhibits
leukocyte adhesion to vascular endothelium.35 To verify this possibility, DC were washed at day 5 of culture to remove IL-13
and then incubated for 2 additional days in the presence of GM-CSF
only. These cells (termed DC w/o IL-13) were compared with conventional
DC cultures exposed to IL-13 for 7 days (DC + IL-13). In vitro
adhesion to monolayers of resting or TNF-activated EC indeed showed
that adhesion of DC w/o IL-13 was higher compared with DC + IL-13 (Fig
1).
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| Fig 1.
Adhesion of cultured DC to monolayers of resting or
TNF-activated EC (10 ng/mL for 24 hours). DC were differentiated from blood monocytes by 5-day culture with 50 ng/mL GM-CSF and 10 ng/mL IL-13. ( ) DC were cultured for 2 additional days in the presence of
GM-CSF and IL-13. ( ) Cells were washed and cultured for 2 additional
days without IL-13. 51Cr-labeled DC were coincubated for 1 hour at 37°C with EC monolayers. Results are expressed as percent of
adherent cells, mean ± SEM of three replicates. Three distinct
experiments are shown.
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Analysis of adhesion molecules, relevant for interaction with the
vascular endothelium, showed that DC + IL-13 expressed lower levels of
CD11a and VLA-4 than DC w/o IL-13 (Fig 2A).It was important to verify that removal of IL-13 in the last 2 days of
culture did not prevent DC differentiation. Fig 2A shows that CD1a and MHC class II were expressed to the same extent in both populations. Figure 2B shows that DC w/o IL-13 were more potent APC for allogeneic T
cells, compared with DC + IL-13 for the whole period of culture. At 1%
APC stimulation index (SI) was 28 and 48 for DC + IL-13 and DC w/o IL-13, respectively. Based on these results all subsequent experiments were performed with DC cultured in the absence of IL-13 for
the last 48 hours.
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| Fig 2.
(A) Characterization of adhesion molecules expressed by
DC. After 5 days in vitro with GM-CSF and IL-13, DC were cultured for 2 additional days in the presence () or absence () of IL-13. Cells
were labeled with the designed MoAb and then with FITC-labeled goat
anti-mouse Ig. (B) Mixed leukocyte reaction (MLR).
Responder cells were allogeneic T lymphocytes depleted of autologous
monocytes and B lymphocytes; they were plated at 1 × 105
cells/well. DC cultured for last 2 days with ( ) or without ( ) of
IL-13 were mixed at the indicated concentrations. 3H-Tdr
was added in the last 18 hours of a 5-day experiment.
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Analysis of expression of 1 and 2 integrins is reported in Fig
3. DC expressed high levels of CD11b and
CD11c and intermediate levels of CD11a. Among 1 integrins, CD49d and
CD49e (VLA-4 and VLA-5) were expressed at high levels. VLA-4 levels
were variable among donors (26.3% ± 13%; range, 3.4 to 77.3; mean
of five experiments). All the cells stained positive for CD61 (3)
and CD31 (PECAM-1), and were negative for CD62L (L-selectin).
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| Fig 3.
Flow cytometric analysis of adhesion molecules expressed
by DC. Cells were labeled with the designed MoAb and then with
FITC-labeled goat anti-mouse Ig.
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The identification of adhesion molecules involved in the binding to
resting EC was performed by using functional blocking MoAb. Anti-CD11a,
anti-CD11b, and anti-CD18 MoAbs partially inhibited adhesion (52%,
64%, and 68%, respectively, in the representative experiments shown
in Fig 4A). It is of interest that CD11c,
although expressed to a very high extent on DC, is not involved in
binding to endothelium. These results were confirmed in a larger series of experiments (mean inhibition with anti-CD18, 61% ± 4%;
mean ± SE of seven experiments).
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| Fig 4.
Molecules involved in the adhesion of DC to resting (A)
and TNF-activated EC (B). 51Cr-labeled DC were preincubated
for 20 minutes at room temperature with the indicated MoAb; thereafter
DC were coincubated with the EC monolayers for 1 hour at 37°C.
Results are expressed as percent of adherent cells, mean ± SEM of
three replicates. **Statistically significant at P < .01 versus medium control.
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On TNF-activated EC expressing high levels of ICAM-1 and VCAM-1, basal
adhesion of DC was increased from 17.3% ± 4.4% to 28.7% ± 5.6%
(mean ± SE of eight experiments). Anti-VLA-4 alone did not inhibit
adhesion (not shown) but the combination of anti-CD18 + anti-VLA-4 was
more inhibitory compared with anti-CD18 alone (Fig 4B), a phenomenon
already observed with other leukocytes.33 These results
show the important role of VLA-4 in leukocyte adhesion, although it is secondary to 2 integrins.
Binding of DC to a natural ECM, derived from cultured EC, or to
purified fibronectin, was higher than to EC monolayers: 52% ± 6%
(mean ± SE of eight experiments) (not shown).
Direct and reverse transendothelial migration.
We previously described an in vitro method to measure transmigration
through monolayers of EC cultured on porous polycarbonate filters.34 In this assay, freshly isolated monocytes showed to have high adhesive (40% ± 13%) and transmigrating ability
(16.8 ± 2; mean ± SE of three experiments) compared with other
leukocytes.34 In vitro cultured DC, differentiated from
monocytes, effectively transmigrated through resting EC monolayers. The
proportion of adhesive and transmigrated cells compared with input
cells in a 1-hour assay was 35.8% ± 2% and 10.6% ± 1.6%,
respectively (mean ± SE; n = 6). Because migration is preceded by
adhesion, anti-CD18 inhibited both adhesion (79%) and transmigration
(75%) in the representative experiment shown in Fig
5. Treatment of EC with anti-CD31 MoAb did
not affect adhesion, but did inhibit transmigration by 38% (Fig
5).
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| Fig 5.
Molecules involved in the transmigration of DC across
resting EC. A porous polycarbonate filter was coated with a monolayer of EC and placed in modified Boyden chamber. 51Cr-labeled
DC were preincubated for 20 minutes at room temperature with the
indicated MoAb and then seeded in the upper compartment and coincubated
with EC for 1 hour at 37°C. Results are expressed as percent of
adherent and transmigrated cells (see Materials and Methods), mean ± SEM of three replicates. **Statistically significant at P < .01 versus medium control.
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| Fig 6.
Adhesion to ECM and reverse transmigration of DC. (A)
Molecules involved in the adhesion of DC to EC-derived matrix (ECM). ECM were prepared by culturing a monolayer of EC on polycarbonate filters for at least 5 days; EC were then stripped by an
NH4OH + Triton solution for 30 seconds. Results are
expressed as percent of adherent cells, mean ± SEM of three
replicates. **Statistically significant at P < .01 versus medium control. (B) Reverse transmigration of DC. A
double-filter system was used. The upper filter was coated with an ECM
and the lower filter was coated with a monolayer of EC placed upside
down. 51Cr-labeled DC were seeded in the upper compartment
of the chamber and coincubated with EC monolayer for 3 hours at 37°C.
Results are expressed as percent of adherent and transmigrated cells
(see Materials and Methods), mean ± SEM of three replicates. Two
independent experiments are shown.
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GM-CSF augments the adhesive properties of monocytes.36
Therefore, experiments were performed with DC washed away of GM-CSF and
rested for 24 hours. Adhesion and transmigration values were not
different from conventional cultures: eg, 28% ± 1% (adhesion) and
7.5% ± 1% (transmigration) for DC with GM-CSF; 27% ± 4% and 8.6% ± 1% for DC rested without GM-CSF (mean ± SE of two
experiments).
Circulating DC precursors migrate from the blood compartment into
tissues. From there, DC reach lymphoid organs via lymph or
blood.6 Therefore, we established an assay to mimic the tissue-to-lymph/blood part of the natural history of DC (reverse transmigration). In this assay the upper filter (of the two-filter system) is coated with ECM, and the lower filter is coated by a
monolayer of EC, placed upside down. As shown in Fig
6A, this natural matrix was highly adhesive
for DC. Anti-VLA-4 + VLA-5 MoAbs or anti-CD29 inhibited most of the
binding (>75% inhibition) while (as expected) anti-CD18 had no
effect. Figure 6B shows the results of two experiments of reverse
transmigration. The mean amount of transmigrated cells relative to
input was 13% ± 4%, which corresponded to 20.8% of adherent cells.
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| Fig 7.
Effect of chemokines on DC transendothelial migration.
Polycarbonate Transwell inserts were coated with a monolayer of EC and
chemoattractants (100 ng/mL) were seeded in the lower compartment. 51Cr labeled DC were placed in the upper compartment and
incubated for 1 hour at 37°C. **Statistically significant at
P < .01 and *P < .05 versus medium control.
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Response of DC to chemokines.
We and others have previously reported that cultured DC migrate in
vitro in response to chemoattractants including formyl peptides and C5a
and a distinct set of CC and CXC chemokines.22-26 Therefore, it was important to assess whether CC chemokines affected the capacity of DC to interact with and migrate across EC monolayers. Polycarbonate Transwell inserts were coated with a monolayer of EC and
chemoattractants were seeded in the lower compartment. As shown in Fig
7, increased migration was induced in response to
MIP-1, RANTES, HCC2/MIP-5, and to a lesser extent to MIP-1 and
MCP-3. These results are in line with our previous findings of
chemotactic response in a classical chemotaxis assay.22,26
| |
DISCUSSION |
The present study is the first analysis of the interaction of DC with
EC and their ECM. DC obtained from monocytes by culture with GM-CSF and
IL-13 expressed CD31, the 2 integrins LFA-1, Mac-1, and p150,95, the
1 integrins VLA-4 and VLA-5, but were negative for other 1
integrins and for L-selectin. They bound resting and activated EC via
LFA-1, Mac-1, and VLA-4, and EC-derived ECM via VLA-4 and VLA-5. DC
were able to migrate across EC monolayers; unlike adhesion,
transendothelial migration involved engagement of CD31. Most
importantly, in view of the trafficking of these cells, DC were able to
perform reverse transmigration.
We and others have reported that DC express receptors for chemokines
and respond to chemotactic signals.22-26,37 Active
chemoattractants included formyl peptides and C5a and a distinct set of
CC and CXC chemokines, which overlaps with but is distinct from those active on other leukocytes.22-26,37 In the present study we
assessed the response of DC to CC chemokines in a transendothelial
migration assay. RANTES, MIP-1, and HCC2/MIP-5 augmented the
transmigration of DC. Intriguingly MCP-3, a strong attractant in a
conventional assay,22,26 had little effect in this assay.
The reason for the dissociation of the capacity of this chemokine to
attract DC in the presence and absence of an EC monolayer is elusive. One could speculate that at least the EC population used here does not
efficiently present MCP-3 to migrating DC.
The interaction of leukocytes with the luminal surface of vascular
endothelium and their passage into tissues has been extensively investigated in vitro in adhesion and transmigration assays. Among leukocytes, lymphocytes and DC have the ability to undergo the reverse
process of migrating from tissue into the lumen of blood or lymphatic
vessels. In an effort to model this tissue-to-lymph/blood component of
the natural history of certain leukocytes we have set up a simple
reverse transmigration assay. As expected, DC were able to migrate
across the basal membrane and then through the endothelial monolayer to
reach the luminal surface. The reverse transmigration assay may
represent a new useful tool to investigate this aspect of leukocyte
trafficking.
DC are heterogeneous populations of BM-derived elements. One pathway of
DC differentiation is closely related to the monocyte-macrophage lineage.17-19,38-41 The population used in the present
study was obtained by culturing monocytes with GM-CSF and IL-13 and
therefore differentiated from monocytic precursors. It is well
established that CD34+ precursors cultured with stem cell
factor, GM-CSF, and TNF give rise to a population containing different
types of DC. At early time points of culture two subsets have been
phenotypically identified: one CD1a+CD14 ,
the other CD1aCD14+. Both subsets eventually
mature into typical DC: the CD1a precursors generate cells with the
typical features of epidermal Langerhans cells, while the
CD14+ precursors, related to the monocytic lineage, express
markers of dermal DC.41 In a limited series of experiments
(n = 4) we tested DC obtained from CD34+ cord blood
cells, cultured as described above. The CD34+-derived DC
behaved similarly to monocyte-derived DC in terms of expression of
adhesion molecules and binding ability. Adhesion to activated EC was
22% ± 3% of input cells and anti-CD18 used in concert with
anti-VLA-4 inhibited up to 80%. Hence, at least some of the results
reported here with monocyte-derived DC may also apply to
CD34+-derived DC.
EC are heterogeneous in terms of morphology and function, both within
the same vascular bed and among different organs.42 Lymphatic EC in particular differ considerably from blood-vessel EC.43 In the present study we used conventional
HUVEC as a model EC population. Further work and the
development of appropriate reliable culture technique will be required
to analyze the interaction of DC with more relevant EC populations such
as those that line lymphatics.
DC undergo complex trafficking patterns.6 Circulating
precursors localize in tissues and this process can be increased by
local inflammation. At epithelial lining surfaces, after antigen capture, DC traffic to lymph nodes via lymphatics. The same route is
followed by DC present in the interstitium of organs such as heart and
kidney; however, these cells can also reach the spleen via the blood
stream. A subset of DC present in the liver can capture circulating
antigen and travel along the lymph/lymph nodes as well as the
blood/spleen route. The molecular pathways of interaction with EC and
ECM proteins described herein are likely to be important in at least
some of the trafficking patterns of DC.
| |
FOOTNOTES |
Submitted November 6, 1997;
accepted February 20, 1998.
G.D. and G.B. have contributed equally to this work.
Supported in part by the National Research Council (Finalized Project
Biotec) and by MURST 40% fund (Project Tumori). The Italian
Association for Cancer Research (AIRC) is gratefully acknowledged.
Address reprint requests to Paola Allavena, MD, Istituto
di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy; e-mail: Allavena{at}irfmn.mnegri.it.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are indebted to Drs A. Minty (Sanofi, Labège, France) and G. Guidi (Novartis, Milan, Italy) for their generous gifts of IL-13 and
GM-CSF, respectively.
| |
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Abstract
Introduction
Abstract