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*
Laboratory of Clinical Investigation and
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a CC chemokine chemotactic
for lymphocytes and dendritic cells. Using anti-serum that we
raised against the N-terminal residues of CCR6, we have characterized
the surface expression of CCR6 on peripheral blood leukocytes and we
have correlated CCR6 expression with responses to MIP-3. We found
that CCR6 was expressed only on memory T cells, including most
4ß7 memory cells and cutaneous
lymphocyte-associated Ag-expressing cells, and on B cells. Accordingly,
chemotaxis of T cells to MIP-3 was limited to memory cells.
Moreover, calcium signals on T cells in response to MIP-3 were
confined to CCR6-expressing cells, consistent with CCR6 being the only
MIP-3 receptor on peripheral blood T cells. Unlike many CC
chemokines, MIP-3 produced a calcium signal on freshly isolated T
cells, and CCR6 expression was not increased by up to 5 days of
treatment with IL-2 or by cross-linking CD3. Despite their surface
expression of CCR6, freshly isolated B cells did not respond to
MIP-3. In addition to staining peripheral blood leukocytes, our
anti-serum detected CCR6 on CD34+ bone marrow
cell-derived dendritic cells. Our data are the first to analyze surface
expression of CCR6, demonstrating receptor expression on
differentiated, resting memory T cells, indicating differences in
receptor signaling on T cells and B cells and suggesting that CCR6 and
MIP-3 may play a role in the physiology of resting memory T cells
and in the interactions of memory T cells, B cells, and dendritic
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The genes for several of the novel chemokines map outside the
previously described chromosomes 4 and 17 chemokine gene clusters (11, 12). A number of these chemokines are also distinguished by targeting
lymphocytes to the exclusion of monocytes and neutrophils, such as the
CXC chemokines IP-10 (6, 13), Mig (7), and BCA-1 (9), and the CC
chemokines TARC (14), PARC/DC-CK-1 (15, 16), macrophage inflammatory
protein (MIP)3-3ß/ELC (17, 18), SLC/6-C-Kine (19, 20), and MIP-3/Exodus/LARC (17, 21, 22).
These latter CC chemokines are also of note in that several can induce
calcium flux and/or chemotaxis and/or integrin-mediated adhesion in
nonactivated T cells (8, 15, 16, 18, 19, 20, 22, 23, 24), consistent with a
role in T cell homeostasis.
Studies of the determinants of chemokine receptor activities on lymphocytes have focused on the regulation of receptor gene and/or protein expression. Such studies have shown that some CC-chemokine receptors (CCR) require cellular activation to induce significant expression (25, 26). Recently data have emerged on the selective expression of chemokine receptors on highly differentiated Th1 and Th2 T cell subsets (27, 28, 29, 30). The data to date on lymphocyte-active chemokines and their receptors suggest that individual receptors and their ligands will be important for particular subpopulations of lymphocytes, distinguished by states of cellular activation and pathways of differentiation.
In experiments to discover new chemokine receptors in activated T
cells, we identified an orphan receptor that we named STRL22 (31). The
same receptor was identified by others (32), and we and others
subsequently reported that STRL22/GPR-CY4/DRY6/CKR-L3 was a receptor
for the CC chemokine MIP-3 (23, 33, 34, 35), and STRL22 was renamed
CCR6.
The mRNA for CCR6 was found to be expressed in lymphoid tissues,
pancreas, and T and B lymphocytes (31, 32, 33, 36). Two groups reported
that the CCR6 mRNA is expressed in CD34+-derived dendritic
cells (34, 35) and that MIP-3 is a chemotactic factor for these
cells (34). The gene for CCR6 is unusual in its location on chrosome
6q27 (31), unlike the genes for CCR1-CCR5 and CCR8, which are clustered
at 3p21. Similarly, CCR6 and MIP-3 are atypical among promiscuous
chemokine receptors and their ligands in that thus far CCR6 is the only
MIP-3 receptor identified, and MIP-3 is the sole ligand described
for CCR6.
MIP-3 (17) was identified by several groups as a result of large
scale sequencing projects and alternatively designated LARC (22),
Exodus (21), and ckß4 (23). MIP-3 is not very closely related to
other CC chemokines, with 20–28% amino acid sequence identity with
other chemokines, and, correspondingly, the MIP-3 gene is not in the
major CC chemokine gene cluster at 17q11.2 but is located instead at
2q33-q37 (22). Northern blotting and analysis of cDNA libraries
revealed expression of the MIP-3 gene in lung, liver, and lymphoid
tissue, and in activated monocytes, endothelial cells, dendritic cells,
fibroblasts, and T cells (17, 21, 22, 23). Besides its activity on
dendritic cells, MIP-3 has been found to be chemotactic for freshly
isolated T cells (22), to be able to inhibit colony formation by
hematopoietic progenitors in vitro (21), and to be able to trigger
adhesion of memory CD4+ T cells to ICAM-1-coated glass
(24).
To investigate the roles of CCR6 and MIP-3 in lymphocyte biology, we
have raised anti-serum against the human CCR6, and we report here
the first studies of surface expression of the receptor, correlating
CCR6 expression on peripheral blood cells with responses to MIP-3.
Our data demonstrate that CCR6 is expressed on diverse subsets of
highly differentiated, resting memory T cells as well as B cells and
dendritic cells, suggesting that CCR6 and MIP-3 may be important for
coordinating interactions among these cells, particularly as part of
the memory response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rabbit anti-sera were raised against the N-terminal domain
of CCR6 using a glutathione S-transferase (GST) fusion
protein as immunogen. A DNA fragment encoding the first 46 residues of
CCR6 and containing BamHI and EcoRI sites at the
5' and 3' ends, respectively, was synthesized using a CCR6 cDNA clone
(31), a standard PCR, and the primers
5'-CGCGGATCCCGACAATGAGCGGGGAATCAATG and
5'-CCGGAATTCCGGCCTGGAGAACTGCCTGACCT. After digestion with
BamHI and EcoRI, the fragment was inserted into
the multiple-cloning site of the pGEX-5X-3 vector (Pharmacia Biotech,
Piscataway, NJ), placing the sequences encoding the N-terminal of CCR6
3' to those encoding the GST of Schistosoma japonicum. The
recombinant plasmid was used to transform the BL21 strain of
Escherichia coli (Novagen, Madsion, WI). Following growth of
bacterial cultures, induction using isopropyl
ß-D-thiogalactoside (IPTG), and lysis of cells
with lysozyme digestion and sonication in the presence of PMSF and
EDTA, the GST/CCR6 fusion protein was purified using Glutathione
Sepharose 4B according to the manufacturer’s protocol (Pharmacia
Biotech) with analysis for size and purity by SDS-PAGE. Rabbits 5145
and 5146 were immunized at multiple sites s.c. with 
200 µg of
fusion protein in CFA followed by boosts using 100 µg of protein in
IFA. Although both rabbits produced Abs against CCR6, all studies shown
below used anti-serum 5146.
Cell culture and leukocyte preparation
Lines of HEK 293 cells transfected with pCEP4 alone or
pCEP4-encoding CCR6 or the orphan receptor STRL33 were cultured as
described previously (23, 36). Elutriated lymphocytes or buffy coats
were collected from normal donors by the Department of Transfusion
Medicine at the National Institutes of Health and PBMC were purified by
Ficoll-Paque (Pharmacia Biotech). For staining of cells in whole blood,
samples were collected from normal donors after informed consent under
a clinical research protocol approved by the National Institute of
Allergy and Infectious Diseases. For preparation of dendritic cells,
bone marrow was aspirated from the iliac crest of a normal donor after
informed consent under a human use protocol approved by the National
Cancer Institute. CD34+ cells were isolated and dendritic
cells were derived as described (37, 38) except that at 6 days cells
were transferred to serum-substituted medium containing 10 ng/ml
granulocyte-macrophage-CSF, 10 ng/ml TNF-, and 1 ng/ml IL-4 (37) and
cells were harvested at 12 days. To activate T lymphocytes, PBMC were
cultured in RPMI 1640 (Life Technologies, Gaithersburg, MD) plus 10%
FBS (Life Technologies) either in the presence of 5 µg/ml of
anti-CD3 Ab (OKT3, OrthoBiotech, Raritan, NJ) for 3 days or in the
presence of 400 U/ml of human rIL-2 (Hoffmann-La Roche, Nutley, NJ) for
5 days.
Flow cytometry
The mAbs used and their suppliers were: FITC-conjugated Ab to
HLA-DR, phycoerythrin (PE)-conjugated Abs to CD19 or HLA-DR,
Cy-5-conjugated Ab to CD14, and allphycocyanin (APC)-conjugated Abs to
CD4 or CD8 from Caltag Laboratory (Burlingame, CA); PE-conjugated Ab to
CD56 from Coulter (Miami, FL); Cy-5-conjugated Abs to CD4 and CD19 from
Sigma (St. Louis, MO) and Life Technologies, respectively;
FITC-conjugated Ab to cutaneous lymphocyte-associated Ag (CLA) (HECA
452) (39) kindly provided by L. J. Picker; FITC-conjugated mAb to
4ß7 (40) kindly provided by A. Lazarovits
and LeukoSite (Cambridge, MA); FITC-conjugated Abs to CD8, CD14, and
CD16, PE-conjugated Abs to CD5, CD4, CD8, CD1a, CD45R0, and CD26, and
Cy-5-conjugated Ab to HLA-DR from PharMingen (San Diego, CA).
To detect surface expression of CCR6 on transfected cells and
leukocytes, indirect immunostaining and flow cytometry were performed.
For staining transfected cells, 106 HEK 293 cells were
resuspended in 100 µl of PBS containing 1% FBS and 10 mM HEPES and
were incubated with preimmune or immune serum to CCR6 (1:10 dilution)
for 1 h at room temperature, washed three times, and stained with
FITC-conjugated, affinity purified F(ab')2 goat
anti-rabbit IgG (Caltag Laboratory) for 15 min at room temperature.
After three washes, cells were analyzed on a FACScan flow cytometer
(Becton Dickinson, San Jose, CA). For staining PBMC, cells were first
incubated with the Fab of anti-Fc
RII mAb IV.3 (Medarex,
Annandale, NJ) followed by preimmune or immune serum to CCR6 at room
temperature for 1 h, washed three times, and stained for 15 min at
room temperature with FITC- or PE-conjugated affinity-purified
F(ab')2 goat anti-rabbit IgG plus two additional mAbs
to leukocyte Ag conjugated with either PE or FITC and Cy-5. After
washing, cells were analyzed for immunofluorescence using either a
FACScan or FACScalibur flow cytometer (Becton Dickinson). For
four-color immunofluorescent analysis, an additional leukocyte marker
conjugated with APC was added.
CCR6 expression on NK cells, monocytes, eosinophils, and neutrophils
was analyzed by whole blood staining. For staining of NK cells and
monocytes, 100 µl of whole blood was preincubated with anti-human
FcRII and anti-human FcRIII for 30 min at 4°C followed by
preimmune serum or immune serum to CCR6 at 4°C for 1 h. Cells
were washed with buffer containing PBS/0.2% BSA/0.1%NaN3
and stained for the NK cell marker CD56, or the monocyte marker CD14,
plus FITC- or PE-conjugated affinity-purified F(ab')2 goat
anti-rabbit IgG. After a 30-min incubation at 4°C, the cells were
washed, and the RBC were lysed using 1x FACS lysing solution
(Becton Dickinson) for 12 min at room temperature. After additional
washing, cells were resuspended in 250 µl of buffer and analyzed for
immunofluorescence using a FACScalibur flow cytometer (Becton
Dickinson).
For staining eosinophils and neutrophils, 100 µl of whole blood was incubated with anti-CD16-FITC for 30 min at 4°C followed by preimmune or immune serum to CCR6 at 4°C for 1 h. After washing, cells were stained with PE-conjugated affinity-purified F(ab')2 goat anti-rabbit IgG for 30 min at 4°C and lysed with 1x FACS lysing buffer as described above. Eosinophils were distinguished from neutrophils based on side scatter and their failing to stain with anti-CD16.
Dendritic cells were preincubated with anti-human FcRII for 15
min at 4°C followed by preimmune serum or immune serum to CCR6 at
4°C for 45 min, followed by FITC-conjugated affinity-purified
F(ab')2 goat anti-rabbit IgG plus anti-CD1a-PE and
anti-HLA-DR-Cy-5 or anti-CD14-Cy-5 and anti-HLA-DR-PE.
Assaying calcium flux
Calcium flux in lymphocytes was measured using multiparameter
FACS analysis as will be described in detail elsewhere (R. L.
Rabin, M. Park, F. Liao, Ruth Swofford, D. Stephany, and J. M.
Farber, manuscript in preparation). Briefly, PBMC were
resuspended in HBSS containing 1%FBS and 10 mM HEPES and loaded with
10 µM Indo-1, AM plus 300 µg/ml pluronic acid (Molecular Probes,
Eugene, Oregon) at 30°C for 45 min with constant shaking. Dynabeads
M-450 CD14 (Dynal, Lake Success, NY) were added during the loading with
dye to remove monocytes. Cells were washed three times, and stained
with fluorophore-conjugated Abs to T cell markers including
anti-CD8 FITC, anti-CD45RO PE, and anti-CD4 Cy-5. Calcium
flux in T cell subsets was detected using a FACSVantage (Becton
Dickinson) dual-laser flow cytometer with a Time Zero injection module
(Cytek, Fremont, CA), and data were analyzed using the Multitime
(Phoenix, AZ) software. MIP-3 was kindly provided by Human Genome
Sciences (Rockville, MD), and stromal cell-derived factor 1 (SDF-1) was
purchased from PeproTech (Rocky Hill, NJ).
Assaying chemotaxis
In vitro chemotaxis assays were performed using the 96-well
ChemoTx #106–5 microplate (Neuro Probe, Gaithersburg, MD) according to
the manufacturer’s protocol. PBMC were resuspended in prewarmed RPMI
1640 containing 1% FBS and 10 mM HEPES at 2 x 106
cells/ml. Chemokines were prewarmed in the above buffer at
concentrations of 1 µg/ml for MIP-3 and 1.5 µg/ml for SDF-1. The
plate was incubated at 37°C in 5% CO2/95% air for
3.5 h. Following incubation, cells on top of the filter were
removed and cold 0.5 mM EDTA in Dulbecco’s phosphate buffered salt
solution was added for 20 min at 4°C before centrifugation to
dislodge any cells on the filter’s underside. The migrated cells in
the bottom wells were collected, counted, and stained for flow
cytometry.
Northern blot analysis
Total RNA from PBMC cultured with or without IL-2 (400 U/ml) as described above was prepared using Trizol reagent (Life Technologies) according to the supplier’s protocol. Then, 30 µg of total RNA were loaded onto a 1.2% agarose-formaldehyde gel, transferred to nitrocellulose, and hybridized with CCR6 32P-labeled probe prepared from a fragment of the CCR6 gene as described (31). The blot’s final wash was in 0.1x SSC, 0.1% SDS at 50°C.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A DNA fragment encoding the N-terminal 46 residues of human CCR6
was ligated to sequences encoding GST from Schistosoma
japonicum to create a sequence encoding a GST fusion protein with
CCR6 residues at its carboxyl terminus. Anti-sera were raised by
immunizing with fusion protein produced in bacteria and purified by
affinity chromatography with Glutathione Sepharose (not shown). Cell
staining using anti-serum 5146 is shown in Fig. 1
. Neither immune nor preimmune serum
stained a control-transfected HEK 293 cell line or an HEK 293 cell line
expressing the orphan receptor, STRL33 (36). Immune, but not preimmune,
serum stained the HEK 293 cells expressing CCR6. Several transfected
HEK 293 cell lines expressing different levels of CCR6 mRNA were
stained with anti-serum 5146, and fluorescent intensities
correlated with levels of CCR6 mRNA (not shown). Using the immune serum
to stain peripheral blood leukocytes revealed that among the
major leukocyte populations CCR6 expression was limited to T cells and
B cells (Fig. 2). The anti-serum
stained 15–40% of CD4+ T cells and 0–14% of
CD8+ T cells, depending on the donor. B cells stained as a
single normally distributed population. We also detected CCR6 on
25% of dendritic cells derived by culturing CD34+ bone
marrow progenitors for 12 days with appropriate cytokines.
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Additional analysis of T cell subsets revealed that for both
CD4+ and CD8+ cells, expression of CCR6 was
limited to the CD45R0+ subset (Fig. 3) and, in particular, the CD45R0 bright
cells. Accordingly, CCR6 was coexpressed with other markers prominent
on memory cells such as CD95 and CD28, although among the
CD4+ memory cells, a higher percentage of
CD28low cells were CCR6+ than was true for the
CD28high cells (not shown). We did not detect significant
numbers of CD25+ and CD69+ PBL, so that all the
CCR6+ cells we identified were CD25- and
CD69- (not shown). In Fig. 3B,
HLA-DR+ cells are CCR6-. Although this pattern
was not found in all donors, in no case did we see a positive
correlation between expression of HLA-DR and CCR6. In contrast, levels
of CCR6 and CD26 were positively correlated. Moreover, almost all the
4ß7+ memory cells and many of
the CLA+ cells were CCR6+.
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Although we found CCR6 expressed on memory cells, we had no
indication from analysis of the freshly isolated PBL that CCR6
expression correlated with cellular activation per se. We investigated
the relationship between CCR6 expression and cellular activation
further by treating cells in vitro with IL-2 for 5 days or with Ab
against CD3 for 3 days. These were similar to protocols that we or
others (25, 33) or we (R.L.R. and J.M.F., unpublished observations)
have used to enhance chemokine receptor expression. As shown in Fig. 4, A and B, neither
5 days of treatment with IL-2 nor 3 days of treatment with the
anti-CD3 Ab OKT3 increased expression of CCR6 on T cells. Because
of a report that CCR6 mRNA levels were increased in T cells by
treatment for 5 days with IL-2 (33), we analyzed mRNA as well and found
no increase with IL-2 treatment (Fig. 4C), consistent with
the results on receptor expression. IL-2-treated cells showed
significant expression of CD25, indicating effective activation (not
shown).
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are limited to memory cells
Analysis of responses of PBL to MIP-3 using the flow cytometer
revealed a MIP-3-induced rise in T cell intracytoplasmic calcium. In
contrast, no calcium flux was seen in B cells (not shown). Responses of
T cell subsets to MIP-3, as shown in Fig. 5, paralleled the subset expression of
CCR6. Fig. 5A demonstrates that calcium flux after exposure
to MIP-3 is limited to the CD45R0+ T cells, with a
higher percentage of CD4+ cells than CD8+ cells
responding. Fig. 5B shows the results of chemotaxis
experiments with MIP-3 and, for comparison, with SDF-1, using a
modified Boyden chamber assay and freshly isolated PBL. As anticipated,
SDF-1 was a potent chemoattractant for PBL, with 30% of input
CD4+ and CD8+ cells moving to lower wells
containing 1.5 µg/ml SDF-1. The CD4+ cells migrating were
both CD45R0+ and CD45R0- so that the ratio of
CD45R0+ to CD45R0- cells in the migrated cells
was equal to that in the input cells. For MIP-3, 20% of input
CD4+ cells and 13% of input CD8+ cells
migrated, and, in contrast to the response to SDF-1, only
CD45R0+ cells migrated so that the ratio of
CD45R0+ to CD45R0- cells in the migrated cells
was 10-fold greater than in the input cells.
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is confined to CCR6-expressing cells
To address more directly the correspondence between the
populations of cells expressing CCR6 and those responding to MIP-3,
we used the flow cytometer to analyze calcium flux in T cells stained
for CCR6. As shown in Fig. 6, all the
MIP-3-responding cells were found among those staining for CCR6.
These findings are consistent with the supposition that CCR6 is the
only receptor for MIP-3 on peripheral blood T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chemokine. Among T cell subsets,
we found expression of CCR6 on both CD4+ and
CD8+ cells, but a higher percentage of the former stained
positive as compared with the latter. Of particular note, CCR6
expression, as well as calcium flux and chemotaxis in response to
MIP-3, were all limited to the CD45R0+ population, i.e.,
memory T cells (41). Furthermore, by analyzing the calcium response to
MIP-3 with freshly isolated PBL that had been stained for CCR6, we
found that all the MIP-3-responding cells were in the CCR6-positive
population. These results are consistent with the supposition that, at
least among T cells, there are no receptors for MIP-3 other than
CCR6, strengthening the data to date on the dedicated relationship
between this ligand and receptor. Together these data establish that
MIP-3 targets exclusively memory cells and that this is based on a
subset-selective expression of CCR6. We have shown that CCR6 is expressed on CD26+ cells. CD26 is a marker with high expression on memory cells (reviewed in 42 . The chemokine receptors CCR2 and CCR5 are expressed primarily on CD26 bright cells (26, 43), and it is the CD26 bright cells that show transendothelial migration both in the absence of added chemokine (44) and in response to MCP-1 and some other CC chemokines (26, 45, 46). With the addition of our data on CCR6, CD26 bright cells are now known to show the highest expression of at least three CCR, suggesting that these cells may be a memory population poised to migrate to inflammatory sites.
Despite the overlap in the patterns of expression for CCR6, CCR5,
and CCR2, our data and those of others suggest that CCR6 plays a
distinct role. In our previous work on CCR6, we noted that MIP-3 had
the somewhat unusual property among CC chemokines of being able to
generate a calcium signal not only in activated T cells but also in
freshly isolated PBL (23), and here we show expression of CCR6, as well
as activity of MIP-3 for both calcium flux and chemotaxis, on
freshly isolated T cells. These findings are consistent with those of
others for chemotaxis to MIP-3 (22) and with the report that
MIP-3 stimulated the adhesion of freshly isolated lymphocytes to
ICAM-1-coated glass (24). Of equal importance, we did not find any
correlation between HLA-DR or other activation markers and CCR6 on PBL,
nor did we see an increase in CCR6 surface expression, CCR6 gene
expression (Fig. 4
), or MIP-3 signaling (F.L., R.L.R., and J.M.F.,
unpublished observations) by activation of T cells in vitro. In fact,
in vitro activation tended to decrease the proportion of
CCR6+ cells, similar to what has been reported recently for
CCR6 expression on dendritic cells exposed to activating agents (47).
This is in contrast to what others, as well as ourselves, have observed
for CCR2 and CCR5, namely an increase in receptor expression and in
chemotactic responses to the relevant ligands with activation (25, 26, 43) (R. L. Rabin, M. Park, F. Liao, R. Swofford, D. Stephany, and
J. M. Farber, unpublished observations). Taken together, the data
suggest that CCR2, CCR5, and likely CCR1 (25) and CXCR3 (13) as well,
function primarily on activated T cells, while CCR6 functions on
resting memory cells.
In the early phases of an inflammatory response, both tissue sites and
lymph node recruit CD4+ memory cells (48) and the
recruitment into lymph node may be particularly important for a recall
response, given the low frequency of memory cells that persist within
the node in the absence of re-exposure to Ag (49, 50). Because the
other lymphocyte receptors for proinflammatory chemokines function best
after cellular activation, a mechanism is needed for the recruitment of
resting cells to sites where activation can occur. Our data suggest
that MIP-3 and CCR6 may have a role in this first stage of
inflammation by recruiting memory cells to sites where they can
encounter Ag, leading in turn to cellular activation, including
enhanced expression and function of chemokine receptors that are
important for trafficking of lymphoblasts to tissue as the immune
response expands. Consistent with this, the MIP-3 gene is
dramatically induced in endothelial cells by TNF (21), an early
mediator of innate immunity, and has also been found to be expressed in
lymph node and appendix (17, 21).
Our data on the failure of T cell activation to up-regulate CCR6
expression is contrary to the effects of IL-2 reported by Baba et al.
(33). While we have no ready explanation for the discrepancy, our
findings are consistent with those reported by Greaves et al., who
reported down-regulation of CCR6 mRNA in PBMC activated with
anti-CD3 and PMA (35). However, we do not think it is likely that T
cell activation is incompatible with expression of CCR6, because
some HLA-DR+ PBL were CCR6+ and many tumor
infiltrating lymphocyte lines grown in IL-2 express CCR6 (36) and
respond to MIP-3 (R.L.R. and J.M.F., unpublished observations).
It is of interest that almost all
4ß7+ memory cells and many
CLA+ cells express CCR6. These represent memory subsets
that home to skin and mucosal sites, respectively (reviewed in Refs. 51
and 52). CLA is up-regulated by IL-12 (53), and consistent with these
findings, E-selectin, which binds CLA (54), mediates recruitment of Th1
cells (55). In contrast, ß7 is induced by TGFß, a
signature cytokine of mucosa-associated lymphoid tissue (56). So CLA
and 4ß7 identify mutually exclusive T cell
subsets (57) that have been activated and differentiated in separate
anatomic compartments and cytokine milieus and will home
appropriately. Therefore, our data suggest that CCR6 is induced on T
cells that were activated in very diverse environments, and that
production of MIP-3 on stimulated endothelium and/or other cells
would be expected to act through CCR6 to recruit these highly
differentiated, resting memory cells to sites of inflammation in both
skin and mucosa.
In addition to expression on T cells, we also found CCR6 on
peripheral blood B cells, consistent with data from our laboratory (36)
and others (33), but contrary to one laboratory’s findings (35) on the
expression of the CCR6 mRNA. However, in contrast to T cells we saw no
reproducible functional effects of MIP-3 on freshly isolated B cells
either in calcium or chemotaxis assays (F.L. and J.M.F., unpublished
observations). This suggests that factors in addition to CCR6
expression may control B cell signaling to MIP-3, and we are
investigating how B cell activation and differentiation may influence
CCR6 responses. It is also possible that there are as yet undiscovered
ligands for CCR6 that may be able to activate the receptor on B cells,
analogous to the recent report that suggests that, unlike other CCR1
ligands, the chemokine leukotactin can activate CCR1 on human
neutrophils (58).
Previous reports had identified CCR6 mRNA expressed in dendritic cells
derived from CD34+ progenitors (34, 35), and our findings
using the anti-CCR6 serum documented expression of the receptor on
many of these cells. A recent report demonstrates that expression of
CCR6 mRNA is down-regulated on immature CD34+ cell-derived
dendritic cells by activating and differentiating agents, and these
authors have suggested that CCR6 is important in recruiting immature
dendritic cells to inflammatory sites (47). Because immature dendritic
cells are efficient at Ag capture and activation specifically of memory
and effector T cells (59), MIP-3 may, by activating CCR6, bring
these cells together at inflammatory sites. While we have not shown
responses by B cells to MIP-3, receptor expression on these cells
raises the possibility that CCR6 may be involved in aggregating, and
perhaps in communication among memory T cells, dendritic cells and B
cells—three critical cellular elements that contact and cooperate with
each other as part of an immune response (60).
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Acknowledgments |
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/ckß4, Gretchen Schwartz for providing
dendritic cells, Louis Picker for the Ab to CLA, Andrew Lazarovits and
LeukoSite for the Ab to 4ß7, Ramya
Gopinath for advice on whole-blood staining, and Meta Snyder for help
with the manuscript. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Joshua M. Farber, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N-228, National Institutes of Health, Bethesda, MD 20892. E-mail address:
3 Abbreviations used in this paper: MIP, macrophage inflammatory protein; STRL, seven transmembrane domain receptors from lymphocytes; CCR, CC-chemokine receptor; GST, glutathione S-transferase; PE, phycoerythrin; APC, allphycocyanin; CLA, cutaneous lymphocyte-associated Ag; SDF-1, stromal cell-derived factor 1; MCP-1, macrophage chemoattractant protein 1; CXCR, CXC-chemokine receptor.
Received for publication June 24, 1998. Accepted for publication September 11, 1998.
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J. H. Kwon, S. Keates, S. Simeonidis, F. Grall, T. A. Libermann, and A. C. Keates ESE-1, an Enterocyte-specific Ets Transcription Factor, Regulates MIP-3alpha Gene Expression in Caco-2 Human Colonic Epithelial Cells J. Biol. Chem., January 3, 2003; 278(2): 875 - 884. [Abstract] [Full Text] [PDF]
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B. Dubois, C. Massacrier, and C. Caux Selective attraction of naive and memory B cells by dendritic cells J. Leukoc. Biol., October 1, 2001; 70(4): 633 - 641. [Abstract] [Full Text] [PDF]
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S. Fujiie, K. Hieshima, D. Izawa, T. Nakayama, R. Fujisawa, H. Ohyanagi, and O. Yoshie Proinflammatory cytokines induce liver and activation-regulated chemokine/macrophage inflammatory protein-3{alpha}/CCL20 in mucosal epithelial cells through NF-{kappa}B Int. Immunol., October 1, 2001; 13(10): 1255 - 1263. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, D. M. Prosser, M. Wiekowski, S. A. Lira, and D. N. Cook Requirement for the Chemokine Receptor Ccr6 in Allergic Pulmonary Inflammation J. Exp. Med., August 20, 2001; 194(4): 551 - 556. [Abstract] [Full Text] [PDF]
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G. Penna, S. Sozzani, and L. Adorini Cutting Edge: Selective Usage of Chemokine Receptors by Plasmacytoid Dendritic Cells J. Immunol., August 15, 2001; 167(4): 1862 - 1866. [Abstract] [Full Text] [PDF]
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A. Izadpanah, M. B. Dwinell, L. Eckmann, N. M. Varki, and M. F. Kagnoff Regulated MIP-3{alpha}/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity Am J Physiol Gastrointest Liver Physiol, April 1, 2001; 280(4): G710 - G719. [Abstract] [Full Text] [PDF]
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K. Sato, H. Kawasaki, H. Nagayama, M. Enomoto, C. Morimoto, K. Tadokoro, T. Juji, and T. A. Takahashi Chemokine Receptor Expressions and Responsiveness of Cord Blood T Cells J. Immunol., February 1, 2001; 166(3): 1659 - 1666. [Abstract] [Full Text] [PDF]
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 P. Conti, R. C. Barbacane, C. Feliciani, and M. Reale Expression and Secretion of RANTES by Human Peripheral Blood CD4+ Cells are Dependent on the Presence of Monocytes Ann. Clin. Lab. Sci., January 1, 2001; 31(1): 75 - 84. [Abstract] [Full Text] [PDF]
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T. Nakayama, R. Fujisawa, H. Yamada, T. Horikawa, H. Kawasaki, K. Hieshima, D. Izawa, S. Fujiie, T. Tezuka, and O. Yoshie Inducible expression of a CC chemokine liver- and activation-regulated chemokine (LARC)/macrophage inflammatory protein (MIP)-3{{alpha}}/CCL20 by epidermal keratinocytes and its role in atopic dermatitis Int. Immunol., January 1, 2001; 13(1): 95 - 103. [Abstract] [Full Text] [PDF]
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D. P. Andrew, N. Ruffing, C. H. Kim, W. Miao, H. Heath, Y. Li, K. Murphy, J. J. Campbell, E. C. Butcher, and L. Wu C-C Chemokine Receptor 4 Expression Defines a Major Subset of Circulating Nonintestinal Memory T Cells of Both Th1 and Th2 Potential J. Immunol., January 1, 2001; 166(1): 103 - 111. [Abstract] [Full Text] [PDF]
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D. J. Fitzhugh, S. Naik, S. W. Caughman, and S. T. Hwang Cutting Edge: C-C Chemokine Receptor 6 Is Essential for Arrest of a Subset of Memory T Cells on Activated Dermal Microvascular Endothelial Cells Under Physiologic Flow Conditions In Vitro J. Immunol., December 15, 2000; 165(12): 6677 - 6681. [Abstract] [Full Text] [PDF]
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B. Serafini, S. Columba-Cabezas, F. Di Rosa, and F. Aloisi Intracerebral Recruitment and Maturation of Dendritic Cells in the Onset and Progression of Experimental Autoimmune Encephalomyelitis Am. J. Pathol., December 1, 2000; 157(6): 1991 - 2002. [Abstract] [Full Text] [PDF]
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K. A. Papadakis, J. Prehn, V. Nelson, L. Cheng, S. W. Binder, P. D. Ponath, D. P. Andrew, and S. R. Targan The Role of Thymus-Expressed Chemokine and Its Receptor CCR9 on Lymphocytes in the Regional Specialization of the Mucosal Immune System J. Immunol., November 1, 2000; 165(9): 5069 - 5076. [Abstract] [Full Text] [PDF]
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E. Schutyser, S. Struyf, P. Menten, J.-P. Lenaerts, R. Conings, W. Put, A. Wuyts, P. Proost, and J. Van Damme Regulated Production and Molecular Diversity of Human Liver and Activation-Regulated Chemokine/Macrophage Inflammatory Protein-3{alpha} from Normal and Transformed Cells J. Immunol., October 15, 2000; 165(8): 4470 - 4477. [Abstract] [Full Text] [PDF]
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R. Krzysiek, E. A. Lefevre, J. Bernard, A. Foussat, P. Galanaud, F. Louache, and Y. Richard Regulation of CCR6 chemokine receptor expression and responsiveness to macrophage inflammatory protein-3alpha /CCL20 in human B cells Blood, October 1, 2000; 96(7): 2338 - 2345. [Abstract] [Full Text] [PDF]
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D. Unutmaz, W. Xiang, M. J. Sunshine, J. Campbell, E. Butcher, and D. R. Littman The Primate Lentiviral Receptor Bonzo/STRL33 Is Coordinately Regulated with CCR5 and Its Expression Pattern Is Conserved Between Human and Mouse J. Immunol., September 15, 2000; 165(6): 3284 - 3292. [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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B. Homey, M.-C. Dieu-Nosjean, A. Wiesenborn, C. Massacrier, J.-J. Pin, E. Oldham, D. Catron, M. E. Buchanan, A. Muller, R. deWaal Malefyt, et al. Up-Regulation of Macrophage Inflammatory Protein-3{alpha}/CCL20 and CC Chemokine Receptor 6 in Psoriasis J. Immunol., June 15, 2000; 164(12): 6621 - 6632. [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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E. P. Bowman, J. J. Campbell, D. Soler, Z. Dong, N. Manlongat, D. Picarella, R. R. Hardy, and E. C. Butcher Developmental Switches in Chemokine Response Profiles during B Cell Differentiation and Maturation J. Exp. Med., April 17, 2000; 191(8): 1303 - 1318. [Abstract] [Full Text] [PDF]
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A. Iwasaki and B. L. Kelsall Localization of Distinct Peyer's Patch Dendritic Cell Subsets and Their Recruitment by Chemokines Macrophage Inflammatory Protein (Mip)-3{alpha}, Mip-3{beta}, and Secondary Lymphoid Organ Chemokine J. Exp. Med., April 17, 2000; 191(8): 1381 - 1394. [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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C.-R. Yu, K. W. C. Peden, M. B. Zaitseva, H. Golding, and J. M. Farber CCR9A and CCR9B: Two Receptors for the Chemokine CCL25/TECK/Ck{beta}-15 That Differ in Their Sensitivities to Ligand J. Immunol., February 1, 2000; 164(3): 1293 - 1305. [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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B. A. Zabel, W. W. Agace, J. J. Campbell, H. M. Heath, D. Parent, A. I. Roberts, E. C. Ebert, N. Kassam, S. Qin, M. Zovko, et al. Human G Protein-Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine-Mediated Chemotaxis J. Exp. Med., November 1, 1999; 190(9): 1241 - 1256. [Abstract] [Full Text] [PDF]
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J. M. Perez-Canadillas, A. Zaballos, J. Gutierrez, R. Varona, F. Roncal, J. P. Albar, G. Marquez, and M. Bruix NMR Solution Structure of Murine CCL20/MIP-3alpha , a Chemokine That Specifically Chemoattracts Immature Dendritic Cells and Lymphocytes through Its Highly Specific Interaction with the beta -Chemokine Receptor CCR6 J. Biol. Chem., July 20, 2001; 276(30): 28372 - 28379. [Abstract] [Full Text] [PDF]
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