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Department of Immunobiology, DNAX Research Institute, Palo Alto, CA 94304
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dendritic cells are bone marrow-derived cells that serve a sentinel role in vivo (3, 4). Immature dendritic cells are distributed throughout many tissues; they are specialized at Ag uptake and processing, but generally express low levels of costimulatory molecules and MHC-peptide complexes on their cell surface (5, 6). Upon stimulation, e.g., by inflammatory signals or CD40 triggering, dendritic cells up-regulate costimulatory molecules, such as CD86 (B7-2), CD80 (B7-1), and CD40 (7). Furthermore, their capability to take up Ag is supplanted by a heightened ability to present Ag (5, 6). Activation of dendritic cells leads to their appearance in T cell-rich areas of secondary lymphoid organs (8), where, as mature dendritic cells, they interface with recirculating T cells. TCR-mediated recognition of specific Ag presented by these dendritic cells subsequently results in T cell priming. Thus, two parallel homing processes, T cell recirculation through lymphoid tissues and Ag-bearing dendritic cell localization to T cell areas in lymphoid tissues, are largely responsible for efficient immune surveillence.
The ability of dendritic cells to migrate from areas of Ag encounter to sites of T cell priming is fundamental to their capacity to elicit an immune response; however, the mechanisms governing this phenomenon remain largely unknown. The molecular mechanisms of T cell recirculation have been the subject of investigation for several decades, and a number of adhesion molecules participating in this process have been defined (9, 10, 11). Recently, the role of chemokines, a large family of low m.w. chemoattractant cytokines, has also been illuminated (12). 6Ckine is a recently discovered chemokine that features an unusually long carboxy-terminal tail containing two additional cysteines (13, 14, 15). It is strongly expressed in the T cell zones of lymph nodes, as well as the high endothelial venules (HEV)2 of lymph nodes and Peyer’s patches (16, 17). 6Ckine has been shown to mediate adhesion (18) as well as chemotaxis (14, 15, 16, 17, 19) of T cells, which suggests that it may be important in lymphocyte homing. Interestingly, 6Ckine is also expressed by the endothelial cells lining lymphatic venules (or vessels) (17), suggesting a role for this chemokine in homing of dendritic cells to secondary lymphoid tissues.
Here, we show evidence that 6Ckine, as well as another CC chemokine receptor-7 (CCR7) ligand, macrophage inflammatory protein (MIP)-3ß, are extremely potent inducers of in vitro- as well as in vivo-derived MHC class IIhigh B7-2high dendritic cell migration. The ability of 6Ckine and MIP-3ß to attract dendritic cells, combined with the expression pattern of these chemokines (13, 14, 15, 16, 17, 20, 21), implicates them as key factors in recruiting dendritic cells into secondary lymphoid organs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bone marrow-derived dendritic cells were generated by culturing bone marrow cell suspensions (22, 23) obtained from female BALB/c mice (Taconic, Germantown, NY) in RPMI 1640 supplemented with 10% FCS, 10 mM HEPES, 1 mM sodium pyruvate, 55 µM 2-ME, L-glutamine, penicillin/streptomycin, 10 µg/ml gentamicin sulfate, 10 ng/ml granulocyte-macrophage (GM)-CSF, and 5 ng/ml IL-4 (23). Cells were cultured for 5–7 days before assay.
Freshly isolated lymph node cells were prepared by homogenizing lymph nodes from BALB/c mice in the presence of 1 mM EDTA to dissociate cell complexes. In some experiments, the cell preparation was enriched for dendritic cells by removing T and B cells using magnetic depletion.
Abs and other reagents
FITC-conjugated anti-I-Ad/I-Ed (2G9), anti-L-selectin (MEL-14), phycoerythrin-conjugated anti-CD11c (HL3), anti-CD45RB (16A), APC-conjugated mAbs directed against B220 (RA3-6B2), CD3 (145-2C11), Gr-1 (RB6-8C5), CD4 (L3T4), and biotinylated anti-B7-2 (GL-1) were from PharMingen (San Diego, CA), as were all relevant isotype control Abs. Biotinylated anti-B7-2 was detected using streptavidin-CyChrome (PharMingen). Magnetic depletions were performed using anti-CD3 (KT3; Serotec, Kidlington, U.K.), anti-B220 (RA3-6B2; PharMingen), and anti-Gr-1 (RB6-8C5; kindly provided by B. Coffman, DNAX, Palo Alto, CA), followed by incubation with anti-rat Ig Dynabeads (Dynal, Oslo, Norway). CD40 stimulation of dendritic cells was achieved using mAb 1C10 (24). All chemokines were from R&D Systems (Minneapolis, MN).
Chemotaxis
All dilutions of cells and chemokines were made in DMEM prepared with low-endotoxin water and containing 1% low-endotoxin BSA (Sigma, St. Louis, MO). Serial dilutions of chemokine were added to 24-well plates. Bone marrow-derived cells (500,000) were added to 5-µm pore size transwell inserts (Costar, Cambridge, MA). Incubation was for 90–120 min at 37°C. When lymph node cells were used, incubation time was extended to 120 min. After removal of the transwell inserts, 104 15-µm microsphere beads (Dynospheres; Bangs Laboratories, Fishers, IN) were added to each well, and cells and beads were transferred to tubes. "Input cells" samples were prepared by mixing 0.5 x 106 cells from the input population with 104 Dynospheres. Cells were stained for flow cytometry to identify CD11c+ MHC class II+ B7-2+ dendritic cells, and to exclude contaminating CD3+, B220+, and Gr-1+ (lineage markers, hereafter collectively referred to as Lin+) cells. Naïve CD4+ T cells were identified as L-selectin+ CD45RBhigh. Samples were analyzed using a FACScalibur (Becton Dickinson, San Jose, CA). Numbers of cells in the input and transmigrated populations were calculated as: (no. of cells acquired/no. of Dynospheres acquired) x 104 Dynospheres/sample. The percentage of input cells that transmigrated was calculated as: (no. of transmigrated cells/no. of input cells) x 100. Cytospins were prepared from the starting as well as the transmigrated cell populations and stained with Giemsa (Sigma).
Ex vivo emigration of dendritic cells in response to 6Ckine and MIP-3ß
Ears from BALB/c mice were aseptically removed and split into dorsal and ventral halves. Both halves were cultured separately in wells of a 24-well plate in medium lacking cytokines, in the absence or presence of 10-8-10-7 M 6Ckine or MIP-3ß. After 18–48 h of culture at 37°C, emigrated cells from each ear were stained for CD11c and I-Ad/I-Ed and analyzed by flow cytometry. Cells were quantitated by adding a defined number of Dynosphere beads to each sample, and emigrated cell numbers were corrected for variations in ear weight. The ultrastructure of emigrated cells was examined in cytospin preparations.
PCR analysis
cDNA libraries prepared from resting bone marrow-derived dendritic cells or bone marrow-derived dendritic cells stimulated overnight with anti-CD40 mAb were subjected to PCR amplification. Plasmid DNA encoding murine (m) CCR6, mCCR7, or mCXCR3 served as control. Primers used were: mCCR6, 907/5'-TCAACCCCGTGTTGTATGCG-3' (forward) and 1063C/5'-TCACTGGTCTTGCCTGGAGATGTAG-3' (reverse); mCCR7, 679/5'-CAGATGGTTTTTGGGTTCCTAGTG-3' (forward) and 914C/5'-TTGAGCTGCTTGCTGGTTTCGCAG-3' (reverse); and mCXCR3, 864/5'CTGTGGTCGAAAAAGCCACG-3' (forward) and 1066C/5'-AGGATGATTCTCTCCGTGAAGATG-3' (reverse). ß-actin was amplified as an internal control. PCR conditions were: 94°C for 2 min, followed by 25 cycles of 94°C for 1 min, 55°C for 2 min, 72°C for 3 min, and 1 cycle of 72°C for 10 min. PCR products were resolved on a 1.2% agarose gel.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As an initial approach to better understand the chemokines potentially involved in dendritic cell migration in vivo, we assessed the chemotactic response of bone marrow-derived dendritic cells in vitro. Bone marrow-derived cells cultured for 5–7 days with GM-CSF and IL-4 were assayed for their ability to migrate across transwells in response to chemokines. Subpopulations of starting and transmigrated cells were then identified and enumerated by flow cytometry. This assay system offers several benefits over other approaches such as Boyden chamber assays, in that 1) large numbers of cells can be efficiently and objectively quantitated, and 2) subsets of cells can be identified without extensive purification procedures.
Because of these advantages, bone marrow cells were not subjected to
any depletion regimen in advance of assaying chemotactic responses, and
the population assayed contained a mixture of several cell types.
Dendritic cells were identified by their distinct morphology in
cytospin preparations (Fig. 1
A,
top) and by their MHC class II+
CD11c+ phenotype (typically 
25–40% of the total cell
population as assessed by flow cytometry; data not shown);
polymorphonuclear cells expressing B220 and/or Gr-1 (Lin+)
were also present (Fig. 1A, top, and data not
shown).
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A,
bottom) and was 70–75% CD11c+Lin-
(data not shown). The dendritic cells generated from bone marrow
progenitors were heterogeneous for their expression of MHC class II and
B7-2, which are up-regulated on activated or mature dendritic cells
(3). Whereas the input DCs were 60–70% MHC class IIhigh
B7-2high and 30–40% MHC class IIlow
B7-2low, the DCs responding to 6Ckine were dramatically
enriched for MHC class IIhigh B7-2high cells,
which were typically 90% (data not shown). 6Ckine was a potent
chemoattractant for MHC class IIhigh B7-2high
dendritic cells over a broad concentration range (Fig. 1B),
routinely attracting 60–90% of this subset of dendritic cells at
optimal concentrations (Fig. 1B). In contrast, only a small
percentage of MHC class IIlow B7-2low dendritic
cells was found in the responding population, and the effective
concentration range was more limited. Incubation of dendritic cells
with 6Ckine did not up-regulate class II MHC or B7-2 expression (data
not shown), ruling out the possibility that MHC class IIlow
B7-2low dendritic cells were attracted and subsequently
became MHC class IIhigh B7-2high. The
specificity of 6Ckine for MHC class IIhigh
B7-2high dendritic cells was further illustrated by the
observation that contaminating Lin+ cells were unresponsive
to 6Ckine, except at high concentrations (Fig. 1B).
Previous reports describing the chemoattractant abilities of
6Ckine have highlighted its effectiveness in T cell migration
(13, 16, 17). In agreement with earlier studies, naïve
CD4+ T cells responded to 6Ckine in the range of
10-6–10-7 M (Fig. 1B). It is
striking that this concentration was 1,000–10,000 times greater than
that needed to elicit a response from bone marrow-derived dendritic
cells.
CD40 ligation leads to up-regulation of costimulatory molecules and activation of dendritic cells (25). To determine whether CD40-mediated activation altered dendritic cell responsiveness to 6Ckine, 5-day bone marrow-derived cultures were depleted of T cells (CD3+), B cells (B220+), and most Gr-1+ cells (primarily granulocytes) and incubated overnight in the presence or absence of anti-CD40 mAb. While CD40 stimulation increased the proportion of dendritic cells that were MHC class IIhigh B7-2high, the percentage of MHC class IIhigh B7-2high dendritic cells responding to 6Ckine was unchanged (data not shown). Therefore, it seems likely that the MHC class IIhigh B7-2high dendritic cells present in unmanipulated cultures represented "mature" dendritic cells that are phenotypically and functionally (with respect to chemotaxis) equivalent to CD40-stimulated dendritic cells.
The CCR7 ligands 6Ckine and MIP-3ß are potent dendritic cell chemoattractants
Several other chemokines have been shown to chemoattract dendritic
cells, such as stromal cell-derived factor (SDF)-1
(26, 27) and
MIP-1 (26, 28, 29), and were therefore compared with
6Ckine in their ability to trigger dendritic cell chemotaxis.
In agreement with previously published results, MHC class
IIhigh B7-2high dendritic
cells responding to human SDF-1 exhibited a more typical
bell shaped curve, in contrast to the extended plateau observed in
response to 6Ckine (Fig. 2). Chemotaxis toward murine
MIP-1 was weak or absent. Both SDF-1 and MIP-1 were capable of
attracting a small percentage of MHC class IIlow
B7-2low dendritic cells. The dose-dependence of the
response to SDF-1 mirrored that of the MHC class IIhigh
B7-2high dendritic cells, while MIP-1 was effective at
10 ng/ml (data not shown).
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and MIP-1, MIP-3ß attracted dendritic cells over a broad
range of concentrations (Fig. 2) and was similar to 6Ckine with respect
to its specificity for MHC class IIhigh
B7-2high dendritic cells (data not shown). Checkerboard analysis
To investigate whether the activity of 6Ckine, MIP-3ß, and
SDF-1 was chemotactic or chemokinetic, checkerboard assays were
performed. When optimal concentrations of each chemokine were added to
the upper, lower, or both chambers in transwell assays, we consistently
observed that each chemokine elicited migration of dendritic cells in a
uniform field (i.e., chemokine was present in both upper and lower
chambers), but not in the presence of a negative gradient (chemokine
present only in the upper chamber) (Fig. 3). However,
the number of dendritic cells that migrated through transwells in a
uniform field was never equivalent to that achieved in the presence of
a positive gradient, suggesting that dendritic cells were sensitive to
chemokine gradients. Similarly, T cells exhibited some degree of
chemokinetic activity in the presence of 10-6 M 6Ckine
(Fig. 3).
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The nearly identical response of dendritic cells to 6Ckine and
MIP-3ß (Fig. 2) strongly suggested that both chemokines were exerting
their effects through CCR7. However, recent evidence that 6Ckine is
also a ligand for CXCR3 (31) raised the possibility that either (or
both) CCR7 or CXCR3 may be involved in the observed chemotaxis of
dendritic cells in response to 6Ckine. To address this question, the
presence of CCR7 and CXCR3 message was assessed in cDNA libraries
prepared from bone marrow-derived dendritic cells cultured in the
presence or absence of anti-CD40 mAb. PCR analysis revealed that
both dendritic cell populations express CCR7, but not CXCR3 (Fig. 4), suggesting that chemotaxis of in vitro-derived
dendritic cells in response to 6Ckine and MIP-3ß is
mediated through their common receptor, CCR7. However, confirmation of
this awaits the availability of neutralizing anti-receptor mAbs.
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These results indicated that 6Ckine and MIP-3ß are effective
chemoattractants for cultured bone marrow-derived dendritic cells.
However, to determine whether these CCR7 ligands were physiologically
relevant dendritic cell chemoattractants, we assessed the chemotactic
response of freshly isolated lymph node cells to 6Ckine and
MIP-3ß in transwell chemotaxis assays. Dendritic cells in the
starting and chemoattracted populations were identified by MHC class
II+ CD11c+ B7-2+ staining. 6Ckine
increased the transmigration of lymph node dendritic cells by 4- to
5-fold (corresponding to 15–25% of input dendritic cells at
optimal chemokine concentrations) (Fig. 5). MIP-3ß was
a consistent, but less potent, chemoattractant for lymph node dendritic
cells (Fig. 5). The differential response to 6Ckine and MIP-3ß was
also observed when CD4+ T cells were analyzed (data not
shown). There was no response to the CXCR3 ligand, Mig (Fig. 5).
Similar results were obtained with dendritic cells isolated from spleen
(data not shown).
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Using a second approach to assess the ability of in vivo-generated
dendritic cells to respond to 6Ckine, we took advantage of the high
density of dendritic cells (Langerhans cells) in skin (7). Mouse ears
were split into dorsal and ventral halves and cultured overnight in
medium without cytokines, in the presence or absence of either
chemokine. The emigration of MHC class II+
CD11c+ cells was consistently augmented by 6Ckine 3- to
12-fold over background levels (Fig. 6). Similar results
were obtained with MIP-3ß (data not shown). Consistent with a large
proportion of emigrated cells staining positively for MHC class II and
CD11c, cytospins indicated that most cells had a dendritic morphology
(Fig. 6B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We now report that 6Ckine is a potent chemoattractant for bone marrow dendritic cells in vitro and for MHC class II+ CD11c+ skin and lymph node dendritic cells ex vivo. We also confirm previous reports (28, 34) that MIP-3ß, another CCR7 ligand, is a chemoattractant for dendritic cells generated in vitro. Furthermore, we extended these findings to show that MIP-3ß is active ex vivo on MHC class II+ CD11c+ dendritic cells derived from skin and lymph nodes. The sensitivity of bone marrow-derived dendritic cells toward 6Ckine and MIP-3ß is 1,000–10,000 times greater than that previously reported for T cells (13, 16, 17, 35).
Dendritic cells within the tissues efficiently capture and process Ag and, following activation, up-regulate cell surface expression of MHC class II and costimulatory molecules such as B7-2, features associated with mature dendritic cells (4). These cells then migrate to lymphoid tissues and become potent APCs capable of T cell priming. 6Ckine (and MIP-3ß) preferentially chemoattracted dendritic cells expressing high levels of MHC class II and B7-2, but were relatively ineffective at attracting MHC class IIlow B7-2low dendritic cells. The selective chemoattraction of dendritic cells displaying a mature phenotype, along with the expression of 6Ckine by lymphatic endothelium, supports a potential role for 6Ckine in mediating migration of mature dendritic cells from the tissue into the draining lymph nodes.
Checkerboard analyses conducted to determine whether the response of
bone marrow-derived dendritic cells toward 6Ckine and MIP-3ß was
chemotactic or chemokinetic showed that although the most effective
migration of dendritic cells was up a gradient of either chemokine,
there was a substantial amount of migration when chemokine was present
in a uniform field (i.e., chemokine present in both the upper and lower
wells of the transwell assay). This effect was also observed using
optimal concentrations of SDF-1. These data suggest that dendritic
cells respond to chemokine-generated signals by increasing their
motility (chemokinesis), but they remain sensitive to a gradient, as
they were never observed to migrate down a chemokine gradient (i.e.,
when chemokine was only present in the upper well). In fact, the number
of dendritic cells migrating down a gradient was often even less than
the number spontaneously migrating in the absence of chemokine (Fig. 3).
Like many chemokines, 6Ckine binds and signals through multiple receptors; however, 6Ckine is unique in its ability to bind both a CC (CCR7; Refs. 30 and 36) and a CXC (CXCR3; 31) receptor. The nearly identical response of dendritic cells to the CCR7 ligands 6Ckine and MIP-3ß strongly suggested that 6Ckine attracts dendritic cells predominantly via CCR7. PCR analysis of bone marrow-derived dendritic cells revealed expression of CCR7, but not CXCR3, supporting the hypothesis that 6Ckine acts through CCR7 in bone marrow-derived dendritic cells.
Chemokine responsiveness and chemokine receptor expression have often
been studied using dendritic cells generated in vitro from precursors
or isolated from blood or other tissue and expanded in vitro. However,
chemokine receptor expression can be affected by culturing dendritic
cells in the presence of cytokines (27, 28, 34). Alterations in
chemokine receptor levels on cultured dendritic cells raised the
possibility that our findings using bone marrow-derived dendritic cells
might not extend to physiologically generated dendritic cells. On the
contrary, we show evidence that not only in vitro-derived, but also in
vivo-derived dendritic cells can respond to 6Ckine and MIP-3ß. First,
freshly isolated, uncultured lymph node dendritic cells responded to
6Ckine and MIP-3ß in transwell chemotaxis assays. The percentage of
lymph node dendritic cells that responded in these assays (15–20%
of the input cells) was lower than that observed for cultured bone
marrow-derived dendritic cells. However, evidence suggests that the
lymph node dendritic cell population is heterogeneous with respect to
surface marker expression and possibly lineage (37, 38), so that it is
possible that 6Ckine may have been active on a particular subset of
lymph node dendritic cells, which were not distinguished in our assays.
While bone marrow-derived dendritic cells may model a subset of in
vivo-derived dendritic cells, a substantial proportion of lymph node
dendritic cells exhibit a chemokine receptor profile that remains to be
elucidated. Interestingly, lymph node dendritic cells (as well as total
CD4+ lymph node cells) responded better to 6Ckine than to
MIP-3ß. The basis for this difference, which was not observed with
bone marrow-derived dendritic cells, is unclear and currently under
investigation.
Further evidence that 6Ckine and MIP-3ß could chemoattract in vivo-generated dendritic cells came from observations that incubation of mouse skin in either chemokine increased emigration of dendritic cells out of the skin. In sum, these data indicate that dendritic cells obtained from lymphoid as well as nonlymphoid tissues are responsive to 6Ckine and MIP-3ß.
Priming of rare T cells specific for a given Ag takes place in secondary lymphoid tissues; dendritic cells are fundamental in presenting Ag to naïve T cells and initiating an immune response. A critical step in this process is the migration of Ag-loaded dendritic cells from nonlymphoid sites of Ag deposition into lymph nodes and Peyer’s patches, a process likely to be guided by chemokines. Our findings show that 6Ckine and MIP-3ß are potent chemoattractants for in vitro-expanded bone marrow-derived dendritic cells and in vivo-generated lymph node and skin dendritic cells. Expression of 6Ckine and MIP-3ß is limited primarily to lymphoid organs; 6Ckine is also expressed in HEV and lymphatic endothelium. Taken together, the evidence prompts the hypothesis that 6Ckine and MIP-3ß are involved in directing dendritic cell homing to, and within, lymphoid tissue in vivo. The ability of these chemokines to attract dendritic cells as well as naïve T cells (17, 35, 39) presents an intriguing model wherein both types of cells are recruited to the same site via the actions of common chemokines, thus promoting the likelihood of their encounter and an ensuing immune response.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: HEV, high endothelial venules; GM-CSF, granulocyte-macrophage CSF; MIP, macrophage inflammatory protein; CCR, CC chemokine receptor; SDF, stromal cell-derived factor; m, murine.
Received for publication December 4, 1998. Accepted for publication December 23, 1998.
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4 ß 7 and LFA-1 in lymphocyte homing to Peyer’s patch-HEV in situ: the multistep model confirmed and refined. Immunity 3:99.[Medline]
chemokine containing six conserved cysteines. J. Immunol. 159:1589.[Abstract]
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L. Riol-Blanco, N. Sanchez-Sanchez, A. Torres, A. Tejedor, S. Narumiya, A. L. Corbi, P. Sanchez-Mateos, and J. L. Rodriguez-Fernandez The Chemokine Receptor CCR7 Activates in Dendritic Cells Two Signaling Modules That Independently Regulate Chemotaxis and Migratory Speed J. Immunol., April 1, 2005; 174(7): 4070 - 4080. [Abstract] [Full Text] [PDF]
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T. Hieronymus, T. C. Gust, R. D. Kirsch, T. Jorgas, G. Blendinger, M. Goncharenko, K. Supplitt, S. Rose-John, A. M. Muller, and M. Zenke Progressive and Controlled Development of Mouse Dendritic Cells from Flt3+CD11b+ Progenitors In Vitro J. Immunol., March 1, 2005; 174(5): 2552 - 2562. [Abstract] [Full Text] [PDF]
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M. Ato, H. Nakano, T. Kakiuchi, and P. M. Kaye Localization of Marginal Zone Macrophages Is Regulated by C-C Chemokine Ligands 21/19 J. Immunol., October 15, 2004; 173(8): 4815 - 4820. |
