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CHEMOKINES
From INSERM U404, Immunité et Vaccination, and
INSERM U503 (C.V.), Lyon, France.
We have studied the impact of B-cell receptor (BCR) or CD40
ligation on the in vitro chemotactic response of tonsillar B cells to 4 chemokines: stromal cell-derived factor (SDF)-1 Development of the humoral response to
T-cell-dependent antigens (Ag) requires a series of orchestrated
movements of T cells, B cells, and antigen-presenting cells within the
lymphoid tissues.1 These movements allow the encounter of
the different cell partners involved in the response. The B-cell
response is initiated in the T zone, where B cells that have taken up
Ag present it to Ag-specific primed T cells. As a result of this
T-cell-B-cell cognate interaction, B cells enter 2 developmental
pathways.2 The first one takes place in the outer part of
the T zone and leads to the production of unmutated plasma cells. It is
also referred to as the extrafollicular reaction. The second one takes place in the follicle, where activated B lymphocytes, most likely originating from the extrafollicular foci, give rise to the germinal center (GC) reaction. During this reaction, B cells undergo a severe
process of positive selection that results in the differentiation of
the best-fit B cells into either memory B cells or mutated plasma
cells. These 2 B-cell subsets then exit the follicle to migrate to
other sites, either to take part into the effector phase of the
response (plasma cells) or to reach the microanatomic niche able to
support their long-term survival (memory B cells and plasma cells). Two
main signals drive the development of B cells during T-dependent
antibody (Ab) responses. The first one is Ag and its signaling through
the B-cell receptor (BCR). The second one is CD40 ligand (CD40L)
induced on T cells during cognate interactions with professional
Ag-presenting cells or Ag-activated B cells. The CD40/CD40L couple is
required for the initiation and maintenance of the GC reaction but not
for the extrafollicular reaction.3-5 Several lines of
evidence from both in vivo and in vitro experiments suggest that the
cellular traffic into and within secondary lymphoid tissues is
controlled by both lymphoid chemokines and cell-cell adhesion
processes. Two important parameters contribute to guide the
movements of B and T cells within the lymphoid tissue during the immune
response. The first one is the restricted location of the sources of
lymphoid chemokines to certain microanatomic sites. The second one is
the pattern of chemokine receptor expression, which is subjected to
regulation depending on the activation or differentiation status of
the cells.
Here we have explored the regulation of the responsiveness of human
tonsil B cells to 4 lymphoid chemokines: stromal cell-derived factor-1
(SDF-1/CXCL12), macrophage inflammatory protein-3 MIP-3 BCA-1 is classically described as a follicle chemokine. This assertion
is based on 2 types of experimental evidence. First, expression of the
BCA-1 protein is prominent in the follicle,14 and recent
results have documented its production by follicular DCs and GC
DCs.15 Second, mice rendered deficient for CXCR5, the
receptor for BCA-1, exhibit an altered follicular architecture and a
default in the recruitment of both B and T cells into these structures
during the humoral response.16
Our results show that virgin and memory B cells have a similar pattern
of in vitro chemotaxis and migrate to the 4 lymphoid chemokines
analyzed here: SDF-1, MIP-3 Antibodies and reagents
Isolation of tonsil B cells
Chemotaxis assay Migration assays were performed essentially as described by Bleul et al.19 We chose to preincubate B cells for 6 hours in complete medium before the migration assays because pilot experiments had shown that this treatment enhanced the number of cells migrating to chemokines without significantly affecting the levels of spontaneous migration. A shorter incubation of the cells (2 hours) resulted consistently in a lower number of cells migrating to the 4 chemokines but did not alter the pattern of B-cell migration. The quantitative difference is probably due to in vivo desensitization20,21 of these cells, which is completely overcome by the 6-hour preculture but not by 2 hours. A total of 5 × 105 cells of the appropriate tonsillar B-cell population were added in the upper 5 µm pore polycarbonate Transwell culture insert of 24-well plates (Costar, Cambridge, MA) in 100 µL HEPES-buffered RPMI 1640 supplemented with 7.5% fetal calf serum. Chemokines were added as 600 µL in the lower chamber. As described in "Results," the concentrations of SDF-1 , MIP-3,
MIP-3 , and BCA-1 required for optimal B-cell migration were 100 ng/mL, 500 ng/mL, 500 ng/mL, and 1 µg/mL, respectively. Cells were
left to migrate for 3 hours, and each migration was performed in
duplicates. To estimate the numbers of B cells migrating to the tested
chemokines, cells in the lower chamber were counted by flow cytometry
for 50 seconds. Percentage of input cells migrating was calculated
after a standard curve obtained using different known concentrations of
B cells that were treated identically to the cells used for migration. In each experiment the number of cells migrating to medium containing no chemokines was considered as the spontaneous migration and therefore
was subtracted from the number of cells migrating to the chemokines
investigated to calculate the percentage of input cells specifically
migrating to each chemokine. The spontaneous migration never exceeded
4% of the input cells. When the phenotype of migrating cells was
required, the cells recovered in the lower chamber as well as the cells
used to elaborate the standard curve were stained with a PE-conjugated
anti-IgD Ab. Virgin and memory B cells were identified as
IgD+ and IgD , respectively.
The inhibition of the B-cell chemotactic response induced by BCR
ligation was calculated as follows: % inhibition
= 100 Cell cultures All cell cultures were performed in complete medium at 37°C in a 5% CO2 atmosphere. Cells were seeded at a density of 3 × 106/mL for different periods of time as indicated in the text.Reverse transcriptase-polymerase chain reaction Isolation of total RNA was performed essentially as described by Chomczynski and Sacchi.22 For reverse transcription, 1 µg RNA was converted into single-stranded DNA by a standard 20 µL RT reaction using random primers P(dN)6 (Boehringer Mannheim) and Superscript kit (RNAseH-MMLV RT; Gibco BRL, Gaithersburg, MD) according to the manufacturer's instructions. One tenth of the total complementary DNA product was amplified in a 50 µL reaction mixture using 1 µM each of sense and antisense primers and 1.25 U Taq polymerase (Perkin Elmer/Cetus, Norwalk, CT). Expression of the-actin messenger RNA was used as a control for RNA integrity and
equal gel loading. PCR products were run on a 1.5% agarose gel,
stained with ethidium bromide, and visualized by ultraviolet illumination.
The amplification primers for CCR6, CCR7, CXCR4, CXCR5, and
Immunofluorescence staining The expression of CCR6, CCR7, CXCR4, and CXCR5 by B cells as well as the phenotype of cells migrating to SDF-1, MIP-3,
MIP-3, and BCA-1 were analyzed by flow cytometry. The distribution
of chemokine receptors was studied by triple staining of freshly isolated B cells. Cells were labeled with anti-CD38, anti-IgD mAbs, and
the appropriate antichemokine receptor Ab. Double labeling for CD38 and
IgD allows discrimination of the 3 main B-cell subsets found in the
tonsil. Virgin B cells are CD38/IgD+, GC B
cells are CD38+/IgD, and memory B cells are
CD38/IgD. For staining, the cells were
resuspended as 107/mL in cold phosphate-buffered saline
supplemented with 10% normal human serum and 0.1% sodium azide. For
the CCR6 staining, B cells were incubated with optimal dilutions of
FITC-coupled anti-CD38, PE-coupled anti-CCR6, and biotinylated anti-IgD
Abs for 15 minutes at 4°C. For the CXCR4 and CXCR5 stainings, cells
were incubated with FITC-coupled anti-CD38, PE-coupled anti-IgD, and
the biotinylated forms of anti-CXCR4 or CXCR5 mAbs. All cells were then
washed twice and incubated with streptavidin coupled to RPE-Cy5 for 15 minutes before flow cytometry analysis. For CCR7 staining, cells were
incubated with FITC-coupled anti-CD38, PE-coupled anti-IgD, and
unconjugated CCR7 Abs. Cells were then washed twice and incubated with
a biotinylated goat anti-mouse IgM Ab before being washed and incubated
with streptavidin coupled to RPE-Cy5 for 15 minutes. For double
staining with CCR6 and CCR7, the memory B cells were first incubated
with PE-coupled anti-CCR6 and the unconjugated anti-CCR7 mAbs, then
with biotinylated goat antimouse IgM, and finally with streptavidin
coupled to RPE-Cy5. When intracytoplasmic staining was required, the
cells were washed in cold phosphate-buffered saline plus 2% fetal calf
serum and permeabilized with PermeaFix (Ortho Diagnostics Systems)
according to the manufacturer's instructions. Once permeabilized, the
cells were washed and treated as for surface staining. All cells
were analyzed on a FACScan flow cytometer (Becton Dickinson,
Heidelberg, Germany).
The relative mean fluorescence intensity (MFI) of the chemokine
receptor stainings was calculated as follows: MFI of chemokine receptor
staining/MFI of irrelevant isotype-matched Ab staining. The percentage
of inhibition of the relative MFI of CCR6, CCR7, CXCR4, and CXCR5
stainings were calculated as follows: % inhibition = 100
CCR6 and CCR7 are heterogeneously expressed by mature B cells Expression of the CCR6, CCR7, CXCR4, and CXCR5 transcripts was analyzed in freshly isolated virgin, GC, and memory B cells by semiquantitative RT-PCR. As shown in Figure 1A, while the messenger RNAs for CCR6, CXCR4, and CXCR5 are present in all 3 B-cell subsets, the CCR7 transcript is absent in GC B cells. To investigate the possible posttranscriptional regulation of chemokine receptor expression, surface expression of CCR6, CCR7, CXCR4, and CXCR5 on B-cell subsets was analyzed by triple immunofluorescence analysis of the unfractionated tonsil B-cell population (Figure 1B). The surface expression of the CXCR4 and CXCR5 proteins matches the results obtained by RT-PCR and confirms that these 2 chemokine receptors are ubiquitously distributed in the mature B-cell compartment. In contrast, CCR6 was subjected to regulation because its expression is lost in the entire GC B-cell population and on approximately half of the memory B-cell subset. Strikingly, the CCR7 protein is undetectable on the surface of any freshly isolated mature B-cell subset. Despite their low or undetectable surface expression on certain B-cell types, both CCR6 and CCR7 were clearly expressed in the cytoplasm of all 3 B-cell subsets considered (Figure 1C). The presence of an intracytoplasmic pool of CCR7 in GC B cells was somehow unexpected because the transcript for CCR7 is not detectable in this B-cell subset.
To investigate whether the lack of CCR7 expression by freshly
isolated tonsil B cells is due to desensitization possibly induced by
previous in vivo contact with either MIP-3
Altogether, these findings indicate that (1) the expression of CCR6 in the mature B-cell compartment is regulated at the posttranslational level, while expression of CCR7 is regulated both at the transcriptional (GC B cells) and posttranslational (memory B cells) levels; (2) the surface expression of both CCR6 and CCR7 is completely repressed in GC B cells; and (3) the surface expression of CCR6 and CCR7 in the memory B cell is heterogeneous. Both virgin and memory B cells migrate to MIP-3 , MIP-3, SDF-1, and BCA-1
in the tonsillar tissue have been previously
documented.6,7 As described above, GC B cells lack
expression of CCR6, the receptor for MIP-3, and CCR7, the receptor
for MIP-3. Furthermore, despite surface expression of CXCR4 and
CXCR5, GC B cells fail to migrate in vitro to SDF-1 and BCA-1 (data not
shown). This defective migration of GC B cells is not imputable to
their apoptosis because their viability when cultured in the presence
of virgin and memory B cells (unfractionated B-cell population) is only
marginally impaired within the time course of the migration experiment.
Thus, because the migratory capacity of GC B cells is strongly
repressed, we decided to compare the in vitro chemotactic response of
virgin and memory B cells to crypt chemokines (MIP-3 and SDF-1), the T-zone chemokine MIP-3, and the B-cell follicle chemokine BCA-1. CD38 B cells isolated by negative selection procedures
were thus exposed for 3 hours to graded concentrations of the 4 chemokines cited above. Their chemotactic response as well as the
phenotype of the cells migrating to these chemokines were investigated
as described in "Materials and methods." As shown in Figure
3, both virgin and memory B cells have
the capacity to migrate in vitro to the 4 chemokines analyzed here. For
all 4 chemokines, the optimal concentration ie, that which attracts
the higher number of cellswas identical for both B-cell subsets. In
contrast for 2 of them (SDF-1 and MIP-3), the amplitude of the
response was higher in memory B cells than in virgin B cells. Whatever
the subset considered, SDF-1 was the chemokine that attracted the
highest number of cells, while MIP-3 was the chemokine with the
lowest B-cell chemotactic activity. Therefore, our data are compatible
with the notion that the chemotactic abilities of virgin and memory B
cells differ quantitatively but not qualitatively.
BCR ligation dramatically alters the chemotaxis pattern of B cells The data shown in Figure 3 indicate that, in the absence of exogenous stimuli, B cells have the potential to migrate to crypt, T-zone, as well as follicle chemokines. Nevertheless, during their response to an antigenic stimulus, B cells are expected to migrate sequentially to distinct microanatomic compartments. Therefore, we next examined whether a surrogate Ag would affect the chemotactic pattern of B cells to the 4 lymphoid chemokines analyzed here. Because both virgin and memory B cells display a similar pattern of responsiveness to MIP-3, SDF-1, MIP-3, and BCA-1, the effects of BCR ligation on
the chemotactic response of B cells was analyzed on a mixed B-cell
population that includes both virgin and memory B cells.
CD38 B cells were first cultured for 6 hours with or
without increasing concentrations of F(ab')2 fragments of
anti-human Ig Abs before being exposed to the optimal concentration of
MIP-3, SDF-1, MIP-3, and BCA-1 as defined in Figure 3. As
shown in Figure 4A, the surrogate Ag
induces a strong dose-dependent inhibition of the chemotactic response
to both crypt chemokines, MIP-3 and SDF-1, and to the follicle
chemokine, BCA-1. In striking contrast, chemotaxis to the T-zone
chemokine, MIP-3, was consistently enhanced by BCR ligation. Figure
4B,C illustrates that the changes of the B cell-chemotactic response to
SDF-1, MIP-3, MIP-3, and BCA-1 induced by the surrogate Ag are
correlated with a modulation of expression of their corresponding
receptors. Altogether, these data indicate that BCR ligation stimulates
the migratory response of B cells to the T-zone chemokine, MIP-3,
while it inhibits their migration to the chemokines produced both in
the crypt and the B-cell follicles.
Ligation of CD40 does not alter the chemotaxis pattern of B cells The CD40/CD40L couple is instrumental in the development of T-dependent Ab responses. The induction and maintenance of the GC reaction are the most important contributions attributed to this pair of molecules during the humoral response. To analyze whether CD40 ligation affects the chemotactic response of B cells, CD38 B cells were preincubated with complete medium,
anti-Ig Abs (10 µg/mL), or soluble trimeric CD40L prior to the
chemotaxis assay. Data in Figure 5 show
that, as opposed to surrogate Ag, CD40L does not modify the pattern of
responsiveness of B cells to chemokines but enhances the
"amplitude" of their response to MIP-3 and BCA-1. While BCR
ligation modulates the B-cell chemotactic response both quantitatively
and qualitatively, CD40 engagement only modulates the amplitude of
this response.
We have also analyzed any possible modulation of the expression of
CCR6, CCR7, CXCR4, and CXCR5 after CD40 cross-linking (data not shown).
Despite the enhancement of B-cell migration to MIP-3 BCR ligation reprograms B cells to migrate to MIP-3 B cells were first exposed for 6 hours to the optimal dose of anti-Ig Abs (10 µg/mL). After the 6-hour
primary culture, the surrogate Ag was washed off, and the cells were
either tested for chemotaxis (T6) or were replaced in culture with
medium containing CD40L for a further 12 hours. As a control,
anti-Ig-pulsed B cells were also recultured for 12 hours in complete
medium without CD40L. At the end of these secondary cultures, the cells
were washed twice and their chemotactic responses assessed (T18). As
expected, after BCR ligation B cells showed little chemotactism toward
SDF-1, MIP-3, and BCA-1, while they migrated strongly toward
MIP-3 (Figure 6A). The removal of
surrogate Ag followed by a further 12-hour culture in complete medium
did not significantly restore their ability to respond to SDF-1 or
MIP-3. Nevertheless, under this culture condition the chemotactic
response to MIP-3 and BCA-1 was strikingly enhanced. The stimulation
of the latter response was the most impressive because 60% of the
input cells migrated to BCA-1 at T18 while only 5% of B cells
responded to this chemokine at T6 in anti-Ig-stimulated cultures. This
pattern of chemotactic response was not further modified when
anti-Ig-activated B cells were exposed to CD40L in the secondary
cultures. This suggests that the signal delivered through CD40 after
the pulse with surrogate Ag has no impact on the migratory response of
B cells. As shown in Figure 6B, the dramatic enhancement of the
chemotactic response to BCA-1 observed in secondary cultures of
anti-Ig-pulsed cultures was not accompanied by a modulation of the
surface expression of CXCR5. Unlike for CXCR5, removal of surrogate Ag
induces an up-regulation of CCR7.
Our experiments show that the anti-Ig-mediated modulation of the
B-cell chemotactic response to BCA-1 is biphasic: suppression after 6 hours of primary culture; strong stimulation at the end of the
secondary culture. We next addressed the question of whether the
enhancement of the B-cell response to BCA-1 in the secondary cultures
of anti-Ig-activated B cells was imputable to removal of the surrogate
Ag or to the late time point at which the chemotaxis assay was
performed. For this purpose, B cells were continuously cultured in the
presence of anti-Ig Abs and were harvested after 6 hours, 12 hours, or
18 hours to be tested for chemotaxis (Figure 6C). The migratory
response of B cells after a 6-hour preculture in complete medium was
used as a control to illustrate the intrinsic migratory capacity of the
B-cell population tested. As expected from our previous observations, a
6-hour stimulation with anti-Ig suppressed the response to SDF-1
In this report, we have studied the regulation of the chemotactic
responses of tonsillar B cells to the lymphoid chemokines MIP-3 The developmental regulation of CCR7 expression on T cells has been
documented previously.23-25 Expression of CCR7 on B cells has been inferred from the observation that both peripheral
blood26 and tonsillar B cells27 weakly
migrate in vitro to MIP-3 In any case, surface CCR6 and CCR7 expression on GC B cells is likely to be repressed by a distinct mechanism because these receptors are not reacquired upon in vitro culture. Down-regulation of the chemokine receptor expression is likely to contribute to retain B cells in the GC until completion of the hypermutation and selection processes to avoid the exit of potentially harmful B cells not suitable for positive selection. It is not yet clear, though, why GC B cells retain an intracytoplasmic pool of CCR7 protein while the expression of the transcript is repressed. In our hands, the expression of CCR6 and CCR7 delineates 2 memory
B-cell subsets. This observation is reminiscent of the heterogeneous expression of these receptors on memory T cells, which has been postulated to distinguish 2 memory subsets with distinct homing capacities.23,28,29 In the tonsil, MIP-3 The distinct phases of the Ab responses to T-dependent Ag take place in
different microanatomic compartments within the secondary lymphoid
tissues. It is therefore expected that B cells exhibit different
migratory behavior depending on their developmental stage. Our results
are in apparent disagreement with this assumption because they show
that virgin and memory B cells display a similar chemotactic pattern.
This unexpected finding may relate to the fact that the in vitro
migration assay is indicative of the chemotactic potential of the cells
but does not necessarily reflect the actual movements of the cells in
vivo. As demonstrated by Foxman et al,34 the trafficking
of cells within a tissue is influenced by the interplay of parameters
such as the concentration of the chemokines, the vicinity of their
sources of production, and the effects of previous chemokine encounters
(desensitization).20,21 Therefore, the in vitro migratory
response of B cells to a set of chemoattractants applied separately
cannot fully predict their orientation in the tissues. Nevertheless,
our results indicate that the chemotactic pluripotentiality of resting
B cells is lost upon BCR-mediated activation, because a surrogate Ag
inhibits B-cell chemotaxis to SDF-1
Unlike BCR ligation, cross-linking of CD40 does not induce dramatic
changes in the pattern of in vitro migration of B cells. The response
to MIP-3
We are grateful to Dr Christophe Caux for careful reading of this manuscript and for all of his helpful comments.
Submitted September 24, 2001; accepted November 5, 2001.
Supported by the Association pour la Recherche sur le Cancer grant 5641. M.C.-P. was originally funded by the Wellcome Trust Fundation and is now the recipient of a grant from La Fondation pour la Recherche Médicale.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Thierry Defrance, INSERM U404, 21 Ave Tony Garnier, 69365 Lyon, Cedex 07, France; e-mail: defrance{at}cervi-lyon.inserm.fr.
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© 2002 by The American Society of Hematology.
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 S. Lopez-Giral, N. E. Quintana, M. Cabrerizo, M. Alfonso-Perez, M. Sala-Valdes, V. G. G. de Soria, J. M. Fernandez-Ranada, E. Fernandez-Ruiz, and C. Munoz Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination J. Leukoc. Biol., August 1, 2004; 76(2): 462 - 471. [Abstract] [Full Text] [PDF]
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M. Inngjerdingen, B. Rolstad, and J. C. Ryan Activating and Inhibitory Ly49 Receptors Modulate NK Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 10 and CXCL12 J. Immunol., September 15, 2003; 171(6): 2889 - 2895. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
(100 × % specific migration of anti-Ig-treated
cells/% specific migration of untreated cells).
