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* Deutsches Rheuma-Forschungszentrum Berlin and
Experimentelle Rheumatologie, Medizinische Klinik, Humboldt University, Berlin, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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48 h, OVA-specific plasma blasts emigrate from
spleen and appear in the bone marrow. Although these migratory cells
have lost their responsiveness to many B cell attracting chemokines,
e.g., CXC chemokine ligand (CXCL)13 (B lymphocyte chemoattractant),
they migrate toward CXCL12 (stromal cell-derived factor 1
),
and toward the inflammatory chemokines CXCL9 (monokine induced by
IFN-
), CXCL10 (IFN--inducible protein 10), and
CXCL11 (IFN-inducible T cell chemoattractant). However, the
responsiveness of plasma blasts to these chemokines is restricted to a
few days after their emigration from the spleen, indicating a role for
these molecules and their cognate receptors, i.e., CXCR3 and CXCR4, in
the regulation of plasma blast migration into the bone marrow and/or
inflamed tissues. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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1 wk in these
foci (3). In contrast, most ASC formed during a memory
response leave the splenic follicles to migrate to and maintain the
humoral immune response either in the bone marrow (4, 5, 6)
or in chronically inflamed tissues (7). Some plasma blasts
migrate into the red pulp of the spleen where these cells also can
persist for long periods of time (8). Chemokines and their
receptors are crucially involved in the control of lymphocyte
trafficking. Although, for example, CXC chemokine ligand (CXCL)12
typically mediates lymphocyte homeostasis, CXCL9, CXCL10, and
CXCL11 are associated with lymphocyte migration into inflamed tissue
(9, 10, 11). It has recently been suggested that CXCR4 is required for normal accumulation of plasma cells in the bone marrow (12). Whether other chemokine receptors besides CXCR4 are involved in the regulation of ASC migration into the bone marrow and which molecules direct ASC into inflamed tissues, has not been clarified yet. In this study, we analyze the localization and chemokine responsiveness of OVA-specific ASC during the time course of a memory response. At the time point of emigration of these cells from the spleen and only for a few days, ASC migrate toward a limited number of chemokines. Besides CXCL12, the only known ligand for CXCR4, these chemokines include all ligands for CXCR3, i.e., the inflammatory chemokines CXCL9, CXCL10, and CXCL11. These results suggest that CXCR3 mediates the attraction of ASC into inflamed tissues. CXCR3 may also contribute supplementary to CXCR4 for the migration of ASC into the bone marrow.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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BALB/c female mice were bred at the animal facility of the Deutsches Rheuma Forschungszentrum Berlin (Berlin, Germany) under specific pathogen-free conditions. At the time point of primary immunization, the animals were 6–8 wk of age. Each mouse received 100 µg OVA (Sigma-Aldrich, Steinheim, Germany) precipitated in aluminum-magnesium-hydroxide (Imject-Alum; Pierce, Rockford, IL; 200 µl in PBS) injected i.p. After 3–6 wk, primed mice were immunized again by injection of 50 µg OVA in 100 µl PBS into the lateral tail vein.
Quantification of OVA-specific IgG ASC by ELISPOT
Single-cell suspensions from bone marrow (femurs) and spleen were filtered through a 70-µm cell strainer (BD Falcon, Bedford, MA), washed, and resuspended in RPMI 1640 medium (Life Technologies, Paisley, U.K.), supplemented with 10% FCS (Invitrogen, Carlsbad, CA), penicillin, streptomycin, and glutamine (complete medium). The standard ELISPOT technique (13) was modified as described, briefly: RIA plates (flat-bottom, high-binding; Corning, Corning, NY) were coated overnight at 4°C with OVA (Sigma-Aldrich) in PBS (5 µg/ml). Then, plates were incubated with PBS containing 3% BSA (Biomol, Hamburg, Germany) 1 h before adding the cells in various dilutions in complete medium. The cells were incubated for 2 h in a humid atmosphere with 5% CO2. Subsequently, cells were removed by vigorous washing with 3% BSA in PBS/0.01% Tween 20 (BSA/PBS/Tween). Between all following steps, plates were washed three times with BSA/PBS/Tween. Biotin-labeled goat anti-mouse IgG (Southern Biotechnology Associates, Birmingham, AL) in PBS (1 µg/ml) was added and plates were incubated for 30 min at room temperature. Following that, 50 µl streptavidin-alkaline phosphatase (Sigma-Aldrich) was added after a 30-min incubation at room temperature. 5-bromo-4-chloro-3-indolyl-phosphate (Sigma-Aldrich) was added to visualize spot formation: 5-bromo-4-chloro-3-indolyl-phosphate per was dissolved in 2-AMP-buffer (95 ml 2-amino-2-methyl-1-propanol, 0.1 ml Triton X-405, 150 mg/ml MgCl2, 900 ml Aqua dest, pH 10.25 adjusted with HCl) at a concentration of 1 mg/ml. The solution was mixed with melted agarose (type I, low electroendosmosis; Sigma-Aldrich) to obtain a final agarose concentration of 0.6%. The mixture was kept at 65°C for 30 min. After addition of the substrate, plates were cooled down to room temperature for solidification of the agarose. The plates were allowed to develop for 2 h at 37°C. Spots were counted under an inverted microscope. Total numbers of OVA-specific ASC in the bone marrow were calculated assuming that both femurs together contain 12.6% of the total bone marrow cells (14).
Chemokines and chemotaxis assay
All chemokines except for CC chemokine ligand (CCL)17
(thymus- and activation-regulated chemokine) were purchased from R&D
Systems (Minneapolis, MN). Recombinant TARC was produced as recently
described (15). TARC-producing cell line was kindly
provided by I. Förster (Technical University of Munich, Munich,
Germany). Chemotaxis assays were performed as described
(16). Briefly, 24-well plates with Transwell inserts
(6.5-mm diameter, 5 µm pores; Corning) and RPMI 1640
medium (Life Technologies) supplemented with 0.5% BSA (low
endotoxin; Sigma-Aldrich) was used (assay medium). The inserts were
coated with 50 µl of murine fibronectin (Invitrogen) at a
concentration of 10 µg/ml in water and incubated for 1 h at
37°C in a humid atmosphere with 5% CO2. The
solution was removed and the inserts were dried for 2 h at 37°C.
Lymphocytes were isolated by gradient centrifugation (Histopaque-1083;
Sigma Diagnostics, St. Louis, MO), washed, counted, and diluted in
assay medium at a final concentration of 5 x
106 cells/ml. Before the chemotaxis assays,
freshly harvested cells were kept in prewarmed (37°C) medium during
the cell isolation procedure, taking 90 min (density gradient
centrifugation and washing). The lower Transwell chamber was filled
with 600 µl of chemokine solution, and 100 µl of the cell
suspension was added to the upper chamber. Cells were allowed to
migrate for 90 min at 37°C in a humid atmosphere with 5%
CO2. Finally, the cells were collected from the
lower Transwell compartment and from control samples containing total
cells before migration. In both fractions, OVA-specific ASC were
quantified by ELISPOT assay as described above and percentages of
migrated cells were calculated.
Functionality of the chemokines was tested by analyzing the migration of CD4-positive cells and eosinophils. Eosinophilic granulocytes were quantified in the input and after migration as follows: the cells were brought on glass slides by cytospin and stained with Giemsa’s solution, then they were assessed and counted under a microscope. The numbers of CD4-positive cells were quantified in the input and migrated population: triplicates of 500 µl aliquots for each chemokine and the medium control were added to a fixed amount of beads (TruCount; BD Biosciences, Mountain View, CA), Abs used for gating (anti-mouse CD4, H129.19) were added, and the number of cells and beads was counted without washing by FACS. Samples were analyzed on a FACSCaliber using CellQuest software (BD Biosciences).
Analysis of OVA-specific plasma cells (PC) by FACS
Single-cell suspensions prepared from bone marrow were washed twice in PBS/0.5% BSA. Cells were incubated with the primary staining reagents at titrated concentrations for 10 min on ice. Primary staining reagents were: FITC-conjugated OVA (OVA was purchased from Sigma-Aldrich and labeled with FITC according to the manufacturer’s protocols), anti-CD138-PE (clone 281-2; BD PharMingen, San Diego, CA), anti-CXCR4-biotin (anti-murine-CXCR4, clone 1D9, a generous gift from R. Förster, Institute of Immunology, Hannover Medical School, Hannover, Germany) was labeled with sulfosuccinimidyl-6-biotinamido-hexanoate (Pierce) according to the manufacturer’s protocols. Biotinylated, isotype-matched rat anti-mouse IL-12 (clone C17.8) has been used as control. For blocking of the CXCR4 staining, cells were preincubated with 100-fold excess of unlabeled anti-CXCR4 Ab. After washing, the cells were stained with streptavidin coupled to allophycocyanin as secondary reagent. Cytometric analysis was performed using a LSR cytometer (BD Biosciences). Samples were stained with propidium iodide. Dead cells, debris, and RBCs were electronically excluded by gating. For analysis, CellQuest software (BD Biosciences) was used.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The numbers of OVA-specific IgG-secreting cells, i.e., plasma
blasts, in spleen and bone marrow were determined by ELISPOT at daily
intervals between days 3 and 6 after secondary immunization (Fig. 1
). In the spleen, where the immune
response was initiated, these cells reached peak numbers at days 4 and
5, before decreasing 10- to 50-fold during the following 2 days. At the
same time, i.e., between days 4 and 6 after secondary immunization,
OVA-specific ASC appeared in the bone marrow where their numbers peaked
at day 6. These data show that the migration of OVA-specific ASC from
spleen into the bone marrow occurred basically within the narrow time
window between days 4 and 6 after secondary immunization. The numbers
of ASC in the blood peaked at that time but were altogether <1000
cells in 1 ml. The obvious lack of accumulation in the blood suggests
that individual plasma blasts circulate only for a short period of time
and are already determined to migrate to their final destinations.
Similar results had earlier been observed after immunization with
lymphocytic choriomeningitis virus, hapten-coupled protein, and sheep
erythrocytes (3, 17, 18, 19), indicating that the rapid PC
formation and migration into the bone marrow observed in our study is a
general phenomenon.
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) at the
optimal concentration ranging between 10 and 100 nM (Fig. 2). About 30% of these cells migrated
toward CXCL9 (monokine induced by IFN-) at a concentration of
100 nM. Migration toward medium alone was <1.5% (basal migration).
Migration toward CXCL9 and CXCL12 was blocked to basal level (<1.5%)
by addition of these chemokines into the upper and lower Transwell
chamber in equivalent concentrations (checkerboard assay), indicating
that the migration could be due to chemotaxis and not to chemokinesis.
Notably, and in accord with two recent reports (12, 21),
no response has been detected to CXCL13 (B lymphocyte chemoattractant),
CCL19 (EBI 1 ligand chemokine), and CCL21 (secondary lymphoid tissue
chemokine), as shown in Fig. 2 and Table I, respectively. These chemokines are
important for B cell localization in the various zones of secondary
lymphoid organs (22).
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-inducible protein 10) and 100 nM
CXCL11 (IFN-inducible T cell chemoattractant), respectively
(data not shown). For all other chemokines tested, no migration above
the basal level could be detected (Table I
). As far as possible, the
functionality of the chemokines used was tested on other cell types, as
shown in Table II. Although our results
cannot formally exclude the possibility for other chemokines to be
involved in the regulation of plasma blast migration, our study has
identified a number of chemokines which can attract plasma blasts
formed in secondary immune responses, i.e., CXCL9, CXCL10, CXCL11, and
CXCL12. The cognate receptors for these chemokines are CXCR3 and CXCR4,
respectively (19, 23, 24, 25). Our results indicate that CXCR3
and CXCR4 are functionally expressed on IgG-secreting plasma blasts
formed in secondary immune responses, at a time point when they leave
the spleen.
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Fig. 1 indicates that OVA-specific plasma blasts, formed within
the first 4–5 days after secondary immunization in the spleen, enter
the bone marrow between days 5 and 6. We tested CXCL12 and CXCL9 for
their potential to attract ASC harvested from bone marrow at various
time points (Fig. 3). At day 6 after
immunization, OVA-specific ASC from bone marrow migrated as well toward
optimal concentrations of CXCL9 and CXCL12 as ASC from spleen. The
percentage of responsive ASC at that time point was not different from
that observed in splenic ASC at day 4. However, at day 12 after
immunization, bone marrow ASC had completely lost their capacity to
migrate toward CXCL9 and CXCL12 at those concentrations optimal for day
4 splenic ASC (Fig. 3), and in concentrations between 0.1 and 300 nM
(data not shown). A 3-h period of preincubation at 37°C before the
chemotaxis assay did not restore the ability of day 12 bone marrow ASC,
nor did this prevent day 6 bone marrow ASC from migrating toward these
chemokines.
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CXCR4 expression on bone marrow PC
To determine whether PC down-regulate surface CXCR4
expression after entry into the bone marrow, CXCR4 expression was
analyzed by FACS on OVA-specific PC at days 6 and 12 after secondary
immunization. OVA-specific PC were identified by staining for the PC
surrogate marker CD138 together with Ag (3, 27). A
population of 0.1% of these cells was detected in the bone marrow
after secondary immunization (Fig. 4A). The staining
"background" in nonimmunized controls was below a frequency of
0.01%. Despite the absence of chemotactic responsiveness toward
CXCL12, CXCR4 is expressed on 77% of the OVA-specific PC derived from
the bone marrow at day 12 after immunization (Fig. 4B).
Specificity of the CXCR4 staining was controlled by staining with an
isotype-matched irrelevant Ab and by incubation with unlabeled Ab
before CXCR4 staining. CXCR4 seemed to be rather up-regulated at day 12
compared with day 6 bone marrow PC. Uncoupling of CXCR4 surface
expression to migration and signaling by an unknown mechanism has been
described for hematopoietic stem cells and B cells, respectively
(28, 29). We assume that CXCR4 on these bone marrow PC may
serve a function different from mediating chemotaxis, possibly
mediating anti-apoptotic signals and supporting cellular survival,
as shown for T cells and peritoneal B cells, respectively (30, 31). The presence of mRNA for CXCR4 has been detected on PC
derived from peripheral lymph nodes (21). However, these
cells did not migrate toward CXCL12. In another report, splenic PC
migrated well toward CXCL12 (12). Our results show that
the chemotactic responsiveness toward CXCL12, but not expression of
CXCR4, depends on the time point after immunization and PC
localization, possibly explaining the apparently contradicting results
on CXCR4 expression and responsiveness to CXCL12.
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Memory Ab titers are produced by a population of PC formed in secondary lymphoid organs migrating and persisting in the bone marrow (6, 19, 32). The capacity of PC to migrate into the bone marrow seems to be critical for the development of persisting Ab responses (33). Chemokines and their cognate receptors usually are important regulators of cell migration. Changes of chemokine responsiveness had been observed during differentiation of PC derived from lymph nodes after primary immunization (21), indicating that these changes may be crucial for emigration from this tissue. To gain information about the regulation of PC migration into the bone marrow, we analyzed the migration and chemokine responsiveness of IgG-secreting PC specific for the protein Ag OVA during the time course of a secondary immune response.
In this study, we show that the responsiveness of plasma
blasts toward CXCR3 and CXCR4 ligands is restricted to the period of
their emigration from spleen and migration into the bone marrow,
suggesting a role for these receptors in the regulation of this
process. It has been shown recently that plasma cells in
CXCR4-deficient fetal liver chimeras accumulate in the bone marrow in
3-fold reduced numbers, showing that this receptor is responsible
for either migration into or retention of PC in the bone marrow
(12). Whether CXCR3 is also involved in directing plasma
blasts into the bone marrow and responsible for the remaining
accumulation of these cells in the bone marrow of CXCR4-deficient
chimeras remains to be elucidated.
In several autoimmune diseases, plasma cells have been detected in chronically inflamed tissue (7, 34, 35). Among these cells are those secreting autoantibodies (7, 34). Through the generation of high local autoantibody concentrations, plasma cells that lodge in the affected inflamed tissue may contribute specifically to the pathogenesis of the disease. We have recently described the accumulation of plasma cells formed in the spleen in the inflamed kidneys of NZB/W F1 mice (36), a model for autoimmune systemic lupus erythematosus (37). Due to the effective migration of plasma blasts into these inflamed organs, plasma cells are found in the kidneys of these mice in numbers comparable to those in the bone marrow. The specificity of the immigrating plasma blasts was not restricted to self-Ag. OVA-specific plasma cells formed a few days after secondary immunization in the spleen lodged in the inflamed kidneys at later time points, indicating that, independent of their specificity, plasma blasts have the capacity to migrate into inflamed tissues (36). In this study, we show that during their migratory phase, such plasma blasts migrate toward the CXCR3 ligands CXCL9, CXCL10, and CXCL11. Using quantitative PCR, we detected an at least 1000-fold increase in the mRNA expression of CXCL10 in the inflamed kidneys of NZB/W mice as compared with the kidneys of healthy controls (data not shown). It has been shown that the ligands for CXCR3 are expressed in various inflamed tissues, including the kidneys of patients suffering from glomerulonephritis (38). It is also well documented that CXCR3 is a key player in the recruitment of T cells to sites of inflammation (9, 39, 40, 41).
CXCR3 has been detected recently on a subset of human
tonsillar PC of unknown descent and designation (42). We
suppose that during their short period of circulation through the
blood, CXCR3 and its ligands crucially contribute to directing plasma
blasts into inflamed tissues. At least 30% of these cells migrate
toward ligands for CXCR3; and therefore, are likely attracted to sites
of inflammation while 60% of circulating plasma blasts migrate
toward CXCL12 (Fig. 2) and possibly can migrate into the bone marrow.
Whether both receptors are expressed together on an individual cell, or
whether CXCR3 and CXCR4 are expressed on distinct plasma blast
subpopulations remains to be investigated.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Rudolf A. Manz, Deutsches Rheuma-Forschungszentrum Berlin, Schumannstrasse 21/22, D-10117 Berlin, Germany. E-mail address: manz{at}drfz.de
3 Abbreviations used in this paper: ASC, Ab-secreting cell; PC, plasma cell; CXCL, CXC chemokine ligand; CCL, CC chemokine ligand.
Received for publication February 25, 2002. Accepted for publication May 24, 2002.
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