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Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Takasaki, Gunma, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1), monocyte chemotactic
protein-3 (MCP-3), and RANTES are active on immature DC but
not on mature DC. Thus, it seems likely that MIP-1, MCP-3, and
RANTES can mediate the migration of immature DC located in peripheral
sites, whereas ELC/MIP-3ß can direct the migration of Ag-carrying DC
from peripheral inflammatory sites, where DC are stimulated to
up-regulate the expression of EBI1/CCR7, to lymphoid organs. It is
postulated that different chemokines and chemokine receptors are
involved in DC migration in vivo, depending on the maturation state of
DC. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines are a large family of small, structurally related cytokines that have four cysteines in highly conserved positions (9, 10, 11, 12). About 30 human chemokines are identified to date and grouped into two major subfamilies, CXC chemokines and CC chemokines, on the basis of the location of the first two cysteines (10, 11, 12). Chemokines have multiple effects and control not only the directed recruitment of the leukocytes, but also HIV infection (13, 14, 15), angiogenesis (16), and hemopoiesis (17, 18). The specific effects of chemokines on target cells are mediated through the seven transmembrane, G protein-coupled receptors (GPCR), which have unique structural features different from other GPCR (19, 20). Cloning strategies using the homologous region of chemokine receptor families have identified many chemokine receptors, including orphan receptors whose natural ligands are unknown. Recently, several novel chemokines have been discovered from expressed sequence tag databases based on the structural feature of chemokine families, and identified as ligands for these orphan receptors (21, 22, 23).
Previous reports showed that CC chemokines like MIP-1, MCP-3, and
RANTES are involved in migration of human cultured DC in vitro, and
that DC differ from other leukocytes in the patterns of response to
chemokines (6, 7, 8). However, the DC that were used in these
studies were mainly immature DC. In this study, we focused on chemokine
receptors selectively expressed in mature DC, because migration of DC
is closely associated with their maturation (5). Here, we
report that the chemokine receptor, EBI1/CCR7, has a unique expression
pattern in DC. EBI1/CCR7 was previously reported as an orphan GPCR
induced by EBV infection in B cells and expressed on activated T and B
cells (24, 25, 26). Recently, the ligand of EBI1/CCR7 was
identified as a novel CC chemokine designated as ELC/MIP-3ß
(21). Here we show that the expression of EBI1/CCR7 is
strikingly up-regulated upon maturation of three distinct DC
populations: 1) mouse bone marrow-derived DC, 2) mouse epidermal
Langerhans cells (LC), and 3) human monocyte-derived DC. Furthermore,
we demonstrate that ELC/MIP-3ß selectively induces increases in
intracellular free Ca2+ concentration
([Ca2+]i) and directional migration of mature
DC but not of immature DC.
Interestingly, the expression of ELC/MIP-3ß is mainly restricted to lymphoid organs such as thymus, spleen, lymph node, and appendix (21, 27). It is tempting to speculate that EBI1/CCR7 might be involved in DC migration from periphery to lymphoid organs after they are stimulated with maturation-inducing inflammatory mediators.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/C mice, 7 to 8 wk old, were purchased from Charles River Japan (Kanagawa, Japan).
Chemokines and cytokines
Recombinant human MIP-1, MCP-3, and RANTES were purchased
from Pepro Tech (Rocky Hill, NJ). Mouse rTNF- and human rIL-4 were
purchased from Genzyme (Cambridge, MA). Purified human and mouse
rGM-CSF and purified human TGF-ß1 were produced in a laboratory of
Kirin Brewery (Gunma, Japan).
Generation of mouse bone marrow-derived DC, epidermal LC, and human monocyte-derived DC
The culture medium was RPMI 1640 (Life Technologies,
Gaithersburg, MD) supplemented with 10% FCS, 10 mM HEPES, 50 µM
2-ME, and 20 µg/ml gentamicin. Mouse bone marrow-derived DC were
obtained as described previously (28, 29). In brief, red
cell- and FcR+ cell-depleted bone marrow cells were
cultured in medium supplemented with GM-CSF (10 ng/ml) and TGF-ß1 (10
ng/ml) for 6 days. To obtain an immature DC-enriched population (D6
BM-DC), FcR- cells were recovered after panning on a human
IgG (Organon Teknika, Durham, NC)-coated Petri dish. D6 BM-DC were
cultured for an additional 2 days with GM-CSF (10 ng/ml) and TNF-
(250 U/ml) to allow further maturation (D8 BM-DC). From 50 to 60% of
D8 BM-DC was mature DC with phenotype of
I-Ahigh/B7-2high as assessed by analyses on
FACScan (Becton Dickinson, San Jose, CA) double stained with
anti-mouse I-Ad mAb (AMS-32.1) and anti-mouse B7-2
mAb (GL1) purchased from PharMingen (San Diego, CA). Epidermal sheets
were prepared by treating the split skin sheets of mouse ears with 1%
trypsin (Cosmo Bio, Tokyo, Japan). Epidermal sheets were floated in
Hanks’ medium supplemented with 10% FCS and agitated gently by
shaking for 1 min. The medium containing single cells (freshly isolated
epidermal cells) from epidermis was recovered. Freshly isolated
epidermal cells were cultured for 3 days and floating cells were
recovered (cultured epidermal cells). Human DC derived from monocytes
were prepared as described previously (30, 31).
Peripheral blood was obtained from normal donors and PBMCs were
prepared by sedimentation in Ficoll-Paque PLUS (Pharmacia Biotech,
Uppsala, Sweden). T cell-depleted PBMCs by neuraminidase-treated
SRBC-rossetting and highly purified CD14+ cells by magnetic
cell sorting with CD14 microbeads (Miltenyi Biotec, Sunnyvale, CA) also
were prepared. These cells were cultured with GM-CSF (50 ng/ml) and
IL-4 (100 ng/ml) for 5 to 7 days (immature DC). Immature DC were
further stimulated with 50% monocyte-conditioned medium (MCM) prepared
by 24-h culture of human IgG panned cells for 3 to 4 days or with LPS
(10 ng/ml) for 24 h to obtain mature DC. The phenotype of immature
and mature DC were assessed by analyses on FACScan stained with mAbs
against HLA-DR, CD1a (Leu-6), and CD14 (Leu-M3) from Becton Dickinson,
CD25 (M-A251) and CD86 (IT2.2) from PharMingen, and CD83 (HB15) from
Immunotech (Marseille, France).
Degenerate oligonucleotide RT-PCR to identify chemokine receptors in mouse mature DC
Total RNA was isolated from the mouse D8 BM-DC using ISOGEN (Nippon Gene, Tokyo, Japan). First-strand cDNA was synthesized from 5 µg total RNA using an oligo(dT) primer with a SuperScript Preamplification System (Life Technologies) following the manufacturer’s recommended protocol. Two microliters of this cDNA was subjected to 40 cycles of PCR in 100 µl reaction mixture containing 0.2 mM each of dNTPs, 2.5 U of TaKaRa Taq (Takara, Kyoto, Japan), 0.55 µg of Taq Start Ab (Clontech, Palo Alto, CA), 1x buffer supplied with the polymerase, and 1 µM of degenerate oligonucleotide primer pair. They were designed based on the conserved sequence of previously known chemokine receptors. Conditions of the PCR were changed depending on each primer pair used. Resultant PCR products were gel purified and cloned into pCR2.1 (Invitrogen, San Diego, CA). Individual clones were sequenced on an Applied Biosystems (Foster City, CA) model 377 DNA sequencer using T3 and T7 primers and analyzed BLAST (National Center for Biotechnology Information, Bethesda, MD).
Cell preparations for RT-PCR analyses
For RT-PCR analyses, cells labeled with appropriate mAbs were sorted on FACS Vantage (Becton Dickinson) using the following criteria to obtain pure cell populations. Mouse B cells (B220+), macrophages (Mac-1+), and granulocytes (Gr-1+) were obtained from bone marrow cells. Mouse T cells (CD4+/CD8- and CD4-/CD8+) were obtained from spleen cells. Mouse immature DC (I-Aintermediate/B7-2low) and mature DC (I-Ahigh/B72high) were obtained from D6 BM-DC and D8 BM-DC, respectively. Mouse immature LC and mature LC were sorted as I-A+ cells from freshly isolated and cultured epidermal cells, respectively. Human B cells, T cells, monocytes, and granulocytes were sorted as CD19+, CD3+, CD14+, and CD66b+ from PBL, respectively. Human immature DC and mature DC were sorted as HLA-DRlow/CD86- and HLA-DRhigh/CD86high cells from cultured monocytes, respectively.
Analyses of chemokine receptor mRNA expression
In Northern blot analysis, 20 µg of total RNA prepared from human immature DC (HLA-DRlow, CD1ahigh, CD14-, CD25-, CD83-, and CD86-)-enriched cells and mature DC (HLA-DRhigh, CD1alow, CD14-, CD25+, CD83+, and CD86high)-enriched cells (>95% pure as assessed by analyses on FACScan) derived from highly purified CD14+ cells were fractionated on denaturing formaldehyde-agarose gel, transferred to a Hybond N+ (Amersham, Les Ulis, France), and immobilized by baking at 80°C for 2 h. Blots were hybridized with 32P-labeled cDNA probes encoding EBI1/CCR7 and ß-actin as a control of RNA loading at 68°C for 1 h in ExpressHyb Hybridization Solution (Clontech) and washed with 2x SSC/0.1% SDS at room temperature for 1 h and followed by 0.1x SSC/0.1% SDS at 63°C for 1 h. In RT-PCR analyses, total RNA isolated from 1 x 105 FACS-purified cells was used for first-strand cDNA syntheses. The cDNA was subjected to 35 cycles of PCR (96°C for 1 min, 58°C for 20 s, and 72°C for 1 min) with specific primers for EBI1/CCR7 ((mouse forward: 5'-ACAGCGGCCTCCAGAAGAACAGCGG, mouse reverse: 5'-TGACGTCATAGGCAATGTTGAGCTG), (human forward: 5'-TCCTTCTCATCAGCAAGCTGTC, human reverse: 5'-GAGGCAGCCCAGGTCCTTGAAG)). As a control, specific primers for ß-actin purchased from Clontech was used.
Preparation of Flag-tagged ELC/MIP-3ß
In order to detect and purify the expressed product, Flag tag (DYKDDDDK) (32) was fused at the C terminus of ELC/MIP-3ß with a four-amino acid linker (SRGG). The cDNA encoding ELC/MIP-3ß-Flag was cloned by RT-PCR from human thymus QUICK-Clone cDNA (Clontech) using ELC/MIP-3ß-modified primers with restriction enzyme sites based on the published sequence (21, 27). The cDNA was cloned into a pSMT201 mammalian cell expression vector (33) and the sequence of the ELC/MIP-3ß-Flag cDNA was verified prior to transfection. Plasmid DNA was transfected by a DEAE-dextran method (34). Briefly, COS 1 cells were seeded at a density of 4 x 106 in a 225-cm2 collagen-coated flask in DMEM with 10% FCS. After 24 h of incubation, cells were washed with DMEM and then transfected with 50 µg of the plasmid DNA in DMEM with 10% NU-SERUM-IV culture supplement (Becton Dickinson), 400 µg/ml DEAE-dextran (Pharmacia), and 100 µM chloroquine (Sigma, St. Louis, MO) for 4 h. After washing cells with DMEM, cells were cultured for 72 h in 50 ml DMEM supplemented with 0.2% BSA, 5 µg/ml bovine insulin, 5 µg/ml human transferrin, 20 µM monoethanolamine, and 25 µM sodium selentite. Culture supernatants of transfected cells were clarified by filtration, concentrated 10-fold using Ultrafree-15 centrifugal filter device Biomax-5k (Millipore, Milford, MA), and purified with anti-Flag M2 Affinity gel (Eastman Kodak, New Haven, CT) as recommended by the supplier. Eluted fractions were neutralized by 1/10 volume of 1 M Tris-HCl (pH 8.0). The purified product was run on a 15/25 gradient gel and transferred to a polyvinylidene difluoride membrane (Millipore). The membrane was blocked with Block-Ace (Dainippon, Osaka, Japan) in TBST (100 mM Tris-HCl (pH7.4), 150 mM NaCl, and 0.1% Tween-20) and incubated with anti-Flag mAb (Eastman Kodak) as the primary mAb and horseradish peroxidase-conjugated goat-anti mouse IgG to a secondary mAb. The Flag-tagged proteins were detected using an enzymatic chemiluminescence kit (ECL Western Blotting Reagent, Amersham). As a control, mock pSMT201-transfected COS1 culture supernatant was processed exactly the same way as described above.
Measurement of intercellular calcium mobilization
Cells were suspended at 5 x 105 cells/ml in recording buffer (5 mM HEPES buffer, pH 7.4 containing 140 mM NaCl, 4 mM KCl, 1.25 mM CaCl2, 1 mM MgCl2, 1 mM NaHPO4, 11 mM glucose, and 0.1% BSA) and loaded with 5 mM fura-2/AM (Dojindo, Kumamoto, Japan) at room temperature for 45 min in the dark. Cells were washed twice, resuspended at 1 to 2 x 105 cells/ml in recording buffer, and 1 ml of cell suspension was used for each assay. Fura-2 fluorescence changes of the freshly loaded cells responding to chemokines were monitored by CAF-110 Intracellar Calcium Measurement System (JASCO, Tokyo, Japan) set at 340 nm excitation and 380 nm and 505 nm emission wavelength. The data are presented as the relative ratio of fluorescence at 340/380 nm.
DC migration assay
The modified method reported by Quin et al. (35) was employed for chemotaxis assay. Assay medium was RPMI 1640 supplemented with 0.1% BSA, 10 mM HEPES, 50 µM 2-ME, and 20 µg/ml gentamicin. Chemokines diluted with assay medium were added to 24-well tissue culture plates (Corning Costar, Cambridge, MA) in a final volume of 600 µl. Transwell culture inserts (Corning Costar) with 6.5-mm diameter and 5.0-µm pore size were inserted into each well and human immature and mature DC (2 x 105 cells for each) derived from highly purified CD14+ cells were added to the top chamber in a final volume of 200 µl. The plate was incubated at 37°C in 5% CO2 for 3 h. The cells migrating to the bottom chamber were recovered and stained with anti-CD86 mAb. A 200-µl aliquot of the total cell suspension was applied to FACScan by acquiring events for a set time period of 60 s and analyzed by differentially counting CD86- cells and CD86+ cells as immature and mature DC, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To identify chemokine receptors in mature DC, we employed a RT-PCR
method with several degenerate oligonucleotide primers designed based
on the amino acid sequence motifs conserved in the chemokine receptor
family. For this purpose, RNA was prepared from mouse D8 BM-DC enriched
with mature DC (50 to 60% pure as assessed by high level expression of
both I-A and B7-2), and reverse transcribed to cDNA. Each PCR product
with appropriate molecular size predicted by the primer pairs was gel
purified, cloned into PCR2.1, and analyzed. The majority of the
resultant clones were previously known chemokine receptors and orphan
putative chemokine receptors. We selected some of them, particularly
the ones that have not been reported to be expressed in DC, to further
analyze the expression pattern between mouse bone marrow-derived
immature and mature DC. Each population was purified by sorting on FACS
Vantage as described in Materials and Methods and analyzed
by RT-PCR using specific primers for each of the genes. Based on the
previous reports, immature DC were sorted as
I-Aintermediate and B7-2low population from D6
BM-DC, i.e., FcR- cells derived from bone marrow cells
cultured with GM-CSF and TGF-ß1 (29). As shown in Figure 1
A, we discovered that EBI1 was selectively expressed in
mature DC but not in immature DC.
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A). This result is consistent
with that of bone marrow-derived DC.
Human EBI1 was originally reported to be an orphan GPCR in Burkitt’s
lymphoma cells and is known to be induced in B cells infected with EBV
and in lymphocytes after activation (24, 25, 26). When the
expression was analyzed in macrophages, granulocytes, B cells, and T
cells, EBI1 was expressed in B cells and T cells in accordance with the
previous reports (24, 25, 26) (Fig. 1B).
Human EBI 1 is induced upon the maturation of human monocyte-derived DC
Human monocyte-derived DC were used to examine whether the
findings in mice could be extended to human DC, because mature
monocyte-derived DC are well characterized in terms of the cell surface
phenotypes and functions (30, 31). Monocytes cultured with
GM-CSF and IL-4 are known to possess typical characters of immature DC
with a high capacity for Ag uptake and low ability for naive T cell
stimulation. Mature DC with high ability in naive T cell stimulation
and low ability in Ag uptake can be induced by further stimulation of
immature DC with MCM or LPS (30, 31). In fact,
monocyte-derived DC obtained in this study following the previously
reported culture methods resulted in a well accepted surface phenotype
of HLA-DRlow, CD1ahigh, CD14-,
CD25-, CD83-, and CD86- for
immature DC and HLA-DRhigh, CD1alow,
CD14-, CD25+, CD83+, and
CD86high for mature DC (Fig. 2). It was also confirmed that mature DC
had 10- to 30-fold higher primary alloMLR-stimulating ability than
immature DC (data not shown).
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A, we discovered that the
expression of EBI1 was strikingly up-regulated after the maturation of
DC. The results were confirmed by RT-PCR on RNA extracted from
FACS-sorted cell population, including T cells, B cells, monocytes,
granulocytes, immature DC, and mature DC (stimulated with MCM). EBI1
was expressed in T cells and was up-regulated in mature DC (Fig. 3B). These results indicate that the expression of EBI1 is
well induced during the maturation of human DC irrespective of the
stimulation, i.e., MCM and LPS.
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In the course of our findings on the expression of EBI1 in mature DC, human ELC/MIP-3ß was cloned and identified as a ligand of EBI1, and EBI1 was designated as CCR7 (21). We tried to confirm whether the selective mRNA expression of EBI1/CCR7 in mature DC described above is correlated with the expression of functional receptors. Previous studies showed that CC chemokines induced a rapid, pertussis toxin (PTX)-sensitive and transient rise of [Ca2+]i in DC (6, 8). In this study, the effect of ELC/MIP-3ß on [Ca2+]i changes in immature and mature DC was evaluated. The ELC/MIP-3ß fused with Flag tag at the C terminus was expressed by COS 1 cells and purified homogeneity by anti-Flag mAb affinity chromatography (ELC/MIP-3ß-Flag). As a control, mock (empty vector)-transfected supernatant was processed in the same way. A single band with the expected molecular size was detected by immunoblotting using anti-Flag mAb in the ELC/MIP-3ß-Flag preparation, but not in mock control (data not shown). The purity and concentration of ELC/MIP-3ß-Flag was estimated from silver staining.
As shown in Figure 4, A and
B, ELC/MIP-3ß-Flag induced a
transient [Ca2+]i in mature DC with complete
desensitization in a dose-dependent fashion (data not shown) but not in
immature DC, while the mock control failed to induce a response in both
types of DC. In addition, the chemokine response was inhibited by
treatment with PTX (data not shown), indicating that the response
induced by ELC/MIP-3ß-Flag in mature DC was mediated through
Gi protein-coupled receptors. These results demonstrate
that mature DC, but not immature DC, selectively express functional
EBI1/CCR7. As it has been reported that RANTES, MIP-1, and MCP-3
induce responses in monocyte-derived DC cultured with GM-CSF and IL-4
(6, 8), we compared the activity of these chemokines in
immature DC and mature DC. RANTES (50 ng/ml at final concentration)
increased [Ca2+]i only in immature DC but not
in mature DC (Fig. 4C). The same results were obtained with
MIP-1 and MCP-3 (data not shown). The fact that immature DC, which
did not respond to ELC/MIP-3ß-Flag, had the potential to respond to
appropriate chemokines suggests that the lack of the response to
ELC/MIP-3ß-Flag in immature DC can be ascribed to the lack of the
expression of EBI1/CCR7. These results indicate that chemokine response
to DC varies with the degree of DC maturation. RANTES, MIP-1, and
MCP-3 react selectively with immature DC, while ELC/MIP-3ß reacts
selectively with mature DC.
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The chemotaxis of DC in response to ELC/MIP-3ß-Flag was
evaluated to further assess the expression of functional EBI1/CCR7. A
transwell migration assay was employed, using the mixed population of
immature and mature DC derived from highly purified human monocytes.
The cells that migrated to the bottom of the chambers were stained with
anti-CD86 mAb to distinguish immature and mature DC on a FACScan.
ELC/MIP-3ß-Flag, but not mock control, selectively induced the
migration of mature DC in a dose-dependent manner, while RANTES
selectively acted on immature DC (Fig. 5). These results are completely
consistent with those in Figure 4. It was shown that EBI1/CCR7 mediates
the migration of mature DC in response to ELC/MIP-3ß-Flag.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we have discovered that EBI1, which has not been
reported to be expressed in DC, is strikingly up-regulated upon the
maturation of DC in three systems: 1) mouse bone marrow-derived DC, 2)
mouse epidermal LC, and 3) human monocyte-derived DC (Figs. 1 and 3).
This was demonstrated by RT-PCR with FACS-sorted cell population in all
systems and by Northern blot analyses with highly purified human DC.
Furthermore, a novel human CC chemokine, ELC/MIP-3ß
(21), which has been identified as the sole ligand of EBI1
(now designated as CCR7) so far tested, selectively induced transient
[Ca2+]i and directional migration of mature
DC but not of immature DC derived from human monocytes (Figs. 4 and 5).
This indicates that functional EBI1/CCR7 is up-regulated along with the
maturation of human DC.
EBI1 was originally identified as an orphan putative chemokine receptor strongly up-regulated in Burkitt’s lymphoma cells after infection with EBV (24). It is also reported that EBI1 is expressed in various lymphoid tissues (24, 25, 26) in which mature DC reside and to which Ag-loaded DC home. Although, human EBI1 has been shown to be expressed in T cells from PBMC as well as in mature DC by RT-PCR, ELC/MIP-3ß failed to induce transient [Ca2+]i in lymphoid cells (CD14+ cell-depleted PBMC) (data not shown). It is likely that the signal detected by RT-PCR in T cells derived from a minor population of activated T cells in peripheral blood, because EBI1 is also reported to be expressed in activated T cells and B cells but not in resting lymphocytes (26).
In contrast to ELC/MIP-3ß, it is interesting to note that CC
chemokines such as MIP-1, MCP-3, and RANTES selectively induced
transient [Ca2+]i increases in immature DC
but not in mature DC (Fig. 4). This is consistent with the previous
report showing that DC derived from monocytes cultured with GM-CSF and
IL-4 or IL-13 (6, 8), i.e., immature DC in this study,
respond to a distinct set of chemokines, including these three
chemokines. Rat respiratory tract DC, which can respond to RANTES, have
been shown to be recruited into airway epithelium during the
inflammatory response (37). It seems likely that MIP-1,
MCP-3, and RANTES are involved in the migration of immature DC to
peripheral inflammatory sites, while ELC/MIP-3ß is involved in the
migration of Ag-loaded DC from the periphery, where the expression of
EBI1/CCR7 are up-regulated by inflammatory stimuli to lymphoid tissues.
In analogy, EBI1/CCR7 might be involved in the induction phase of
delayed-type hypersensitivity response. Previous findings showing that
expression of ELC/MIP-3ß is mainly restricted to lymphoid organs
(21, 27) support this idea. Studies in experimental
animals have shown that LPS, GM-CSF, IL-1, and TNF- are involved in
DC migration from nonlymphoid tissues to lymphoid organs
(38, 39, 40). As all these signals are also involved in DC
maturation, the possibility that the induction of EBI1/CCR7 on DC
should be considered as one of the mechanisms.
Recently, CCR6 has been reported to be expressed in human
CD34+ progenitor-derived DC and lung DC, but not in
monocyte-derived DC (41, 42). Furthermore, CCR6 is
particularly expressed in one of the two intermediates derived from
CD34+ progenitor cells, i.e., CD1a+-derived
Langerhans-like cells but not CD14+-derived
dermal/interstitial-like DC (42). In this sense, CCR6
expression seems to vary with the subset of DC. In contrast, CCR7 is
expressed on three different tissues of mature DC. The expression of
CCR6 is down-regulated in CD34+ progenitor-derived DC upon
stimulation with PMA and ionomycin, whereas the expression of CCR7 is
up-regulated upon maturation of DC (42). Similarly, CCR7
is up-regulated upon T cell activation, while CCR6 is down-regulated
(42). There are also several similarities between the two
receptors. It is reported that CCR6 is most closely related to CCR7 in
terms of phylogenetic relationship among known chemokine receptors and
a number of orphan receptors (41). Furthermore, the
ligands of these receptors, LARK/MIP-3 and ELC/MIP-3ß, share
features that are distinct among most CC chemokines (21, 27). Most CC chemokines bind to more than one chemokine
receptor, while LARK/MIP-3 and ELC/MIP-3ß are the sole ligands so
far tested for their respective receptors. Most human CC chemokine
genes are clustered on chromosome 17q11.2, while the genes of
LARK/MIP-3 and ELC/MIP-3ß are located on chromosome 2q33-37 and
9p13, respectively. Collectively, it is tempting to speculate that CCR6
and CCR7 might have evolved in close relation to control migration of
DC and lymphocytes by their reciprocal expression, depending on cell
maturation and activation status.
In summary, we have discovered that the expression of EBI1/CCR7 is strikingly up-regulated upon the maturation of DC and that ELC/MIP-3ß, the ligand of EBI1/CCR7, selectively induces the directional migration of mature DC. It is proposed that EBI1/CCR7 plays a crucial role in DC migration, especially from periphery to lymphoid organs. EBI1/CCR7 as a DC chemokine receptor may be a potential target of immune intervention in graft rejection, allergy, and autoimmune diseases.
Note added in proof: After acceptance of this manuscript, Dieu et al. (43) and Sozzani et al. (44) reported the expression of CCR7 along with the maturation of DC and their responsiveness to ELC/MIP-3ß.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cells; [Ca2+]i, intracellular free calcium; GM, granulocyte/macrophage; GPCR, G protein-coupled receptors; LC, Langerhans cells; MIP, macrophage inflammatory protein; MCM, monocyte conditioned medium; MCP, monocyte chemotactic protein; PTX, pertussis toxin.
Received for publication March 17, 1998. Accepted for publication May 11, 1998.
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G. Li, S. Basu, M.-K. Han, Y.-J. Kim, and H. E. Broxmeyer Influence of ERK activation on decreased chemotaxis of mature human cord blood monocyte-derived dendritic cells to CCL19 and CXCL12 Blood, April 15, 2007; 109(8): 3173 - 3176. [Abstract] [Full Text] [PDF]
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H. Chunsong, H. Yuling, W. Li, X. Jie, Z. Gang, Z. Qiuping, G. Qingping, Z. Kejian, Q. Li, A. E. Chang, et al. CXC Chemokine Ligand 13 and CC Chemokine Ligand 19 Cooperatively Render Resistance to Apoptosis in B Cell Lineage Acute and Chronic Lymphocytic Leukemia CD23+CD5+ B Cells J. Immunol., November 15, 2006; 177(10): 6713 - 6722. [Abstract] [Full Text] [PDF]
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 M. Stolk, M. Leon-Ponte, M. Merrill, G. P. Ahern, and P. J. O'Connell IP3Rs are sufficient for dendritic cell Ca2+ signaling in the absence of RyR1 J. Leukoc. Biol., September 1, 2006; 80(3): 651 - 658. [Abstract] [Full Text] [PDF]
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Q. Wang, Y. Liu, J. Wang, G. Ding, W. Zhang, G. Chen, M. Zhang, S. Zheng, and X. Cao Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor J. Immunol., August 15, 2006; 177(4): 2175 - 2185. [Abstract] [Full Text] [PDF]
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 N. F. Pinheiro Jr., M. D. R. Hermida, M. P. Macedo, J. Mengel, A. Bafica, and W. L. C. dos-Santos Leishmania Infection Impairs {beta}1-Integrin Function and Chemokine Receptor Expression in Mononuclear Phagocytes Infect. Immun., July 1, 2006; 74(7): 3912 - 3921. [Abstract] [Full Text] [PDF]
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S. Benhamron, H. Nechushtan, I. Verbovetski, A. Krispin, G. Abboud-Jarrous, E. Zcharia, E. Edovitsky, E. Nahari, T. Peretz, I. Vlodavsky, et al. Translocation of Active Heparanase to Cell Surface Regulates Degradation of Extracellular Matrix Heparan Sulfate upon Transmigration of Mature Monocyte-Derived Dendritic Cells. J. Immunol., June 1, 2006; 176(11): 6417 - 6424. [Abstract] [Full Text] [PDF]
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W. Cao, P. Tan, C. H. Lee, H. Zhang, and J. Lu A transforming growth factor-beta-induced protein stimulates endocytosis and is up-regulated in immature dendritic cells Blood, April 1, 2006; 107(7): 2777 - 2785. [Abstract] [Full Text] [PDF]
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M. H. Jang, N. Sougawa, T. Tanaka, T. Hirata, T. Hiroi, K. Tohya, Z. Guo, E. Umemoto, Y. Ebisuno, B.-G. Yang, et al. CCR7 Is Critically Important for Migration of Dendritic Cells in Intestinal Lamina Propria to Mesenteric Lymph Nodes J. Immunol., January 15, 2006; 176(2): 803 - 810. [Abstract] [Full Text] [PDF]
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D. F. Legler, P. Krause, E. Scandella, E. Singer, and M. Groettrup Prostaglandin E2 Is Generally Required for Human Dendritic Cell Migration and Exerts Its Effect via EP2 and EP4 Receptors J. Immunol., January 15, 2006; 176(2): 966 - 973. [Abstract] [Full Text] [PDF]
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 K. Vermaelen and R. Pauwels Pulmonary Dendritic Cells Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 530 - 551. [Abstract] [Full Text] [PDF]
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 O. Fainaru, D. Shseyov, S. Hantisteanu, and Y. Groner Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease PNAS, July 26, 2005; 102(30): 10598 - 10603. [Abstract] [Full Text] [PDF]
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S. Paoletti, V. Petkovic, S. Sebastiani, M. G. Danelon, M. Uguccioni, and B. O. Gerber A rich chemokine environment strongly enhances leukocyte migration and activities Blood, May 1, 2005; 105(9): 3405 - 3412. [Abstract] [Full Text] [PDF]
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 S. Yamagami, P. Hamrah, K. Miyamoto, D. Miyazaki, I. Dekaris, T. Dawson, B. Lu, C. Gerard, and M. R. Dana CCR5 Chemokine Receptor Mediates Recruitment of MHC Class II-Positive Langerhans Cells in the Mouse Corneal Epithelium Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1201 - 1207. [Abstract] [Full Text] [PDF]
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 T. Mori, J. Kim, T. Yamano, H. Takeuchi, S. Huang, N. Umetani, K. Koyanagi, and D. S.B. Hoon Epigenetic Up-regulation of C-C Chemokine Receptor 7 and C-X-C Chemokine Receptor 4 Expression in Melanoma Cells Cancer Res., March 1, 2005; 65(5): 1800 - 1807. [Abstract] [Full Text] [PDF]
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S. de Noronha, S. Hardy, J. Sinclair, M. P. Blundell, J. Strid, O. Schulz, J. Zwirner, G. E. Jones, D. R. Katz, C. Kinnon, et al. Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein Blood, February 15, 2005; 105(4): 1590 - 1597. [Abstract] [Full Text] [PDF]
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D. M. Jawdat, E. J. Albert, G. Rowden, I. D. Haidl, and J. S. Marshall IgE-Mediated Mast Cell Activation Induces Langerhans Cell Migration In Vivo J. Immunol., October 15, 2004; 173(8): 5275 - 5282. [Abstract] [Full Text] [PDF]
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Y. Akasaki, G. Liu, N. H. C. Chung, M. Ehtesham, K. L. Black, and J. S. Yu Induction of a CD4+ T Regulatory Type 1 Response by Cyclooxygenase-2-Overexpressing Glioma J. Immunol., October 1, 2004; 173(7): 4352 - 4359. [Abstract] [Full Text] [PDF]
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U. Ritter, F. Wiede, D. Mielenz, Z. Kiafard, J. Zwirner, and H. Korner Analysis of the CCR7 expression on murine bone marrow-derived and spleen dendritic cells J. Leukoc. Biol., August 1, 2004; 76(2): 472 - 476. [Abstract] [Full Text] [PDF]
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 H. Takeuchi, A. Fujimoto, M. Tanaka, T. Yamano, E. Hsueh, and D. S. B. Hoon CCL21 Chemokine Regulates Chemokine Receptor CCR7 Bearing Malignant Melanoma Cells Clin. Cancer Res., April 1, 2004; 10(7): 2351 - 2358. [Abstract] [Full Text] [PDF]
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W. Matsuyama, M. Faure, and T. Yoshimura Activation of Discoidin Domain Receptor 1 Facilitates the Maturation of Human Monocyte-Derived Dendritic Cells Through the TNF Receptor Associated Factor 6/TGF-{beta}-Activated Protein Kinase 1 Binding Protein 1{beta}/p38{alpha} Mitogen-Activated Protein Kinase Signaling Cascade J. Immunol., October 1, 2003; 171(7): 3520 - 3532. [Abstract] [Full Text] [PDF]
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L. Skelton, M. Cooper, M. Murphy, and A. Platt Human Immature Monocyte-Derived Dendritic Cells Express the G Protein-Coupled Receptor GPR105 (KIAA0001, P2Y14) and Increase Intracellular Calcium in Response to its Agonist, Uridine Diphosphoglucose J. Immunol., August 15, 2003; 171(4): 1941 - 1949. [Abstract] [Full Text] [PDF]
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 N. E. Annels, C. E.T. da Costa, F. A. Prins, A. Willemze, P. C.W. Hogendoorn, and R. M. Egeler Aberrant Chemokine Receptor Expression and Chemokine Production by Langerhans Cells Underlies the Pathogenesis of Langerhans Cell Histiocytosis J. Exp. Med., May 19, 2003; 197(10): 1385 - 1390. [Abstract] [Full Text] [PDF]
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T. Akahoshi, T. Sasahara, R. Namai, T. Matsui, H. Watabe, H. Kitasato, M. Inoue, and H. Kondo Production of Macrophage Inflammatory Protein 3{alpha} (MIP-3{alpha}) (CCL20) and MIP-3{beta} (CCL19) by Human Peripheral Blood Neutrophils in Response to Microbial Pathogens Infect. Immun., January 1, 2003; 71(1): 524 - 526. [Abstract] [Full Text] [PDF]
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I. Verbovetski, H. Bychkov, U. Trahtemberg, I. Shapira, M. Hareuveni, O. Ben-Tal, I. Kutikov, O. Gill, and D. Mevorach Opsonization of Apoptotic Cells by Autologous iC3b Facilitates Clearance by Immature Dendritic Cells, Down-regulates DR and CD86, and Up-regulates CC Chemokine Receptor 7 J. Exp. Med., December 16, 2002; 196(12): 1553 - 1561. [Abstract] [Full Text] [PDF]
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H. Matsue, C. Yang, K. Matsue, D. Edelbaum, M. Mummert, and A. Takashima Contrasting Impacts of Immunosuppressive Agents (Rapamycin, FK506, Cyclosporin A, and Dexamethasone) on Bidirectional Dendritic Cell-T Cell Interaction During Antigen Presentation J. Immunol., October 1, 2002; 169(7): 3555 - 3564. [Abstract] [Full Text] [PDF]
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G. J. Randolph Is Maturation Required for Langerhans Cell Migration? J. Exp. Med., August 19, 2002; 196(4): 413 - 416. [Full Text] [PDF]
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M. Nakamura, M. Iwahashi, M. Nakamori, K. Ueda, I. Matsuura, K. Noguchi, and H. Yamaue Dendritic Cells Genetically Engineered to Simultaneously Express Endogenous Tumor Antigen and Granulocyte Macrophage Colony-stimulating Factor Elicit Potent Therapeutic Antitumor Immunity Clin. Cancer Res., August 1, 2002; 8(8): 2742 - 2749. [Abstract] [Full Text] [PDF]
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G. Page, S. Lebecque, and P. Miossec Anatomic Localization of Immature and Mature Dendritic Cells in an Ectopic Lymphoid Organ: Correlation with Selective Chemokine Expression in Rheumatoid Synovium J. Immunol., May 15, 2002; 168(10): 5333 - 5341. [Abstract] [Full Text] [PDF]
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K. Mashino, N. Sadanaga, H. Yamaguchi, F. Tanaka, M. Ohta, K. Shibuta, H. Inoue, and M. Mori Expression of Chemokine Receptor CCR7 Is Associated with Lymph Node Metastasis of Gastric Carcinoma Cancer Res., May 1, 2002; 62(10): 2937 - 2941. [Abstract] [Full Text] [PDF]
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R. M. Steinman and M. C. Nussenzweig Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance PNAS, January 1, 2002; (2002) 231606698. [Abstract] [Full Text] [PDF]
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A. Bouchon, C. Hernandez-Munain, M. Cella, and M. Colonna A DAP12-mediated Pathway Regulates Expression of CC Chemokine Receptor 7 and Maturation of Human Dendritic Cells J. Exp. Med., October 15, 2001; 194(8): 1111 - 1122. [Abstract] [Full Text] [PDF]
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S.-A. Kellermann and L. M. McEvoy The Peyer's Patch Microenvironment Suppresses T Cell Responses to Chemokines and Other Stimuli J. Immunol., July 15, 2001; 167(2): 682 - 690. [Abstract] [Full Text] [PDF]
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S.-f. Hsu, P. J. O'Connell, V. A. Klyachko, M. N. Badminton, A. W. Thomson, M. B. Jackson, D. E. Clapham, and G. P. Ahern Fundamental Ca2+ Signaling Mechanisms in Mouse Dendritic Cells: CRAC Is the Major Ca2+ Entry Pathway J. Immunol., May 15, 2001; 166(10): 6126 - 6133. [Abstract] [Full Text] [PDF]
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Z. Dembic, J.-A. Rottingen, J. Dellacasagrande, K. Schenck, and B. Bogen Phagocytic dendritic cells from myelomas activate tumor-specific T cells at a single cell level Blood, May 1, 2001; 97(9): 2808 - 2814. [Abstract] [Full Text] [PDF]
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P. Hjelmström Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines J. Leukoc. Biol., March 1, 2001; 69(3): 331 - 339. [Abstract] [Full Text]
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M. M. Al-Alwan, G. Rowden, T. D. G. Lee, and K. A. West Fascin Is Involved in the Antigen Presentation Activity of Mature Dendritic Cells J. Immunol., January 1, 2001; 166(1): 338 - 345. [Abstract] [Full Text] [PDF]
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S.-i. Hashimoto, T. Suzuki, S. Nagai, T. Yamashita, N. Toyoda, and K. Matsushima Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression Blood, September 15, 2000; 96(6): 2206 - 2214. [Abstract] [Full Text] [PDF]
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M.-C. Dieu-Nosjean, C. Massacrier, B. Homey, B. Vanbervliet, J.-J. Pin, A. Vicari, S. Lebecque, C. Dezutter-Dambuyant, D. Schmitt, A. Zlotnik, et al. Macrophage Inflammatory Protein 3{alpha} Is Expressed at Inflamed Epithelial Surfaces and Is the Most Potent Chemokine Known in Attracting Langerhans Cell Precursors J. Exp. Med., September 5, 2000; 192(5): 705 - 718. [Abstract] [Full Text] [PDF]
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X. Cao, W. Zhang, T. Wan, L. He, T. Chen, Z. Yuan, S. Ma, Y. Yu, and G. Chen Molecular Cloning and Characterization of a Novel CXC Chemokine Macrophage Inflammatory Protein-2{gamma} Chemoattractant for Human Neutrophils and Dendritic Cells J. Immunol., September 1, 2000; 165(5): 2588 - 2595. [Abstract] [Full Text] [PDF]
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D. Yang, Q. Chen, S. Stoll, X. Chen, O. M. Z. Howard, and J. J. Oppenheim Differential Regulation of Responsiveness to fMLP and C5a Upon Dendritic Cell Maturation: Correlation with Receptor Expression J. Immunol., September 1, 2000; 165(5): 2694 - 2702. [Abstract] [Full Text] [PDF]
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P. Brossart, A. Zobywalski, F. Grünebach, L. Behnke, G. Stuhler, V. L. Reichardt, L. Kanz, and W. Brugger Tumor Necrosis Factor {{alpha}} and CD40 Ligand Antagonize the Inhibitory Effects of Interleukin 10 on T-Cell Stimulatory Capacity of Dendritic Cells Cancer Res., August 1, 2000; 60(16): 4485 - 4492. [Abstract] [Full Text]
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M. Larsson, D. Messmer, S. Somersan, J.-F. Fonteneau, S. M. Donahoe, M. Lee, P. R. Dunbar, V. Cerundolo, I. Julkunen, D. F. Nixon, et al. Requirement of Mature Dendritic Cells for Efficient Activation of Influenza A-Specific Memory CD8+ T Cells J. Immunol., August 1, 2000; 165(3): 1182 - 1190. [Abstract] [Full Text] [PDF]
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D. Yang, Q. Chen, O. Chertov, and J. J. Oppenheim Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells J. Leukoc. Biol., July 1, 2000; 68(1): 9 - 14. [Abstract] [Full Text]
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H. Nagase, M. Miyamasu, M. Yamaguchi, T. Fujisawa, K. Ohta, K. Yamamoto, Y. Morita, and K. Hirai Expression of CXCR4 in Eosinophils: Functional Analyses and Cytokine-Mediated Regulation J. Immunol., June 1, 2000; 164(11): 5935 - 5943. [Abstract] [Full Text] [PDF]
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C. Murdoch and A. Finn Chemokine receptors and their role in inflammation and infectious diseases Blood, May 15, 2000; 95(10): 3032 - 3043. [Abstract] [Full Text] [PDF]
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M. Hirao, N. Onai, K. Hiroishi, S. C. Watkins, K. Matsushima, P. D. Robbins, M. T. Lotze, and H. Tahara CC Chemokine Receptor-7 on Dendritic Cells Is Induced after Interaction with Apoptotic Tumor Cells: Critical Role in Migration from the Tumor Site to Draining Lymph Nodes Cancer Res., April 1, 2000; 60(8): 2209 - 2217. [Abstract] [Full Text]
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J. Gosling, D. J. Dairaghi, Y. Wang, M. Hanley, D. Talbot, Z. Miao, and T. J. Schall Cutting Edge: Identification of a Novel Chemokine Receptor That Binds Dendritic Cell- and T Cell-Active Chemokines Including ELC, SLC, and TECK J. Immunol., March 15, 2000; 164(6): 2851 - 2856. [Abstract] [Full Text] [PDF]
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K. Inaba, S. Turley, T. Iyoda, F. Yamaide, S. Shimoyama, C. R. e Sousa, R. N. Germain, I. Mellman, and R. M. Steinman The Formation of Immunogenic Major Histocompatibility Complex Class II-Peptide Ligands in Lysosomal Compartments of Dendritic Cells Is Regulated by Inflammatory Stimuli J. Exp. Med., March 13, 2000; 191(6): 927 - 936. [Abstract] [Full Text] [PDF]
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 P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hebert, R. Horuk, K. Matsushima, L. H. Miller, J. J. Oppenheim, and C. A. Power International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors Pharmacol. Rev., March 1, 2000; 52(1): 145 - 176. [Abstract] [Full Text] [PDF]
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R. M. Steinman, S. Turley, I. Mellman, and K. Inaba The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic Cells J. Exp. Med., February 7, 2000; 191(3): 411 - 416. [Full Text] [PDF]
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R. Josien, H.-L. Li, E. Ingulli, S. Sarma, B. R.Wong, M. Vologodskaia, R. M. Steinman, and Y. Choi TRANCE, a Tumor Necrosis Factor Family Member, Enhances the Longevity and Adjuvant Properties of Dendritic Cells In Vivo J. Exp. Med., February 7, 2000; 191(3): 495 - 502. [Abstract] [Full Text] [PDF]
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R.A. Warnock, J.J. Campbell, M.E. Dorf, A. Matsuzawa, L.M. McEvoy, and E.C. Butcher The Role of Chemokines in the Microenvironmental Control of T versus B Cell Arrest in Peyer's Patch High Endothelial Venules J. Exp. Med., January 3, 2000; 191(1): 77 - 88. [Abstract] [Full Text] [PDF]
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H. Hasegawa, T. Nomura, M. Kohno, N. Tateishi, Y. Suzuki, N. Maeda, R. Fujisawa, O. Yoshie, and S. Fujita Increased chemokine receptor CCR7/EBI1 expression enhances the infiltration of lymphoid organs by adult T-cell leukemia cells Blood, January 1, 2000; 95(1): 30 - 38. [Abstract] [Full Text] [PDF]
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A.-S. Charbonnier, N. Kohrgruber, E. Kriehuber, G. Stingl, A. Rot, and D. Maurer Macrophage Inflammatory Protein 3{alpha} Is Involved in the Constitutive Trafficking of Epidermal Langerhans Cells J. Exp. Med., December 20, 1999; 190(12): 1755 - 1768. [Abstract] [Full Text] [PDF]
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H. D. Byrnes, H. Kaminski, A. Mirza, G. Deno, D. Lundell, and J. S. Fine Macrophage Inflammatory Protein-3{beta} Enhances IL-10 Production by Activated Human Peripheral Blood Monocytes and T Cells J. Immunol., November 1, 1999; 163(9): 4715 - 4720. [Abstract] [Full Text] [PDF]
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M. T. Crowley, C. R. Reilly, and D. Lo Influence of Lymphocytes on the Presence and Organization of Dendritic Cell Subsets in the Spleen J. Immunol., November 1, 1999; 163(9): 4894 - 4900. [Abstract] [Full Text] [PDF]
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D. Yang, O. M. Z. Howard, Q. Chen, and J. J. Oppenheim Cutting Edge: Immature Dendritic Cells Generated from Monocytes in the Presence of TGF-{beta}1 Express Functional C-C Chemokine Receptor 6 J. Immunol., August 15, 1999; 163(4): 1737 - 1741. [Abstract] [Full Text] [PDF]
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J. G. Cyster Chemokines and the Homing of Dendritic Cells to the T Cell Areas of Lymphoid Organs J. Exp. Med., February 1, 1999; 189(3): 447 - 450. [Full Text] [PDF]
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R. M. Steinman and M. C. Nussenzweig Inaugural Article: Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance PNAS, January 8, 2002; 99(1): 351 - 358. [Abstract] [Full Text] [PDF]
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