By
From the * Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire
03756; the Department of Immunology, Inflammation and Cell Biology, Biogen, Cambridge,
Massachusetts 02142; and the § Serono Pharmaceutical Research Institute, CH-1228
Plan-les-Ouates, Geneva, Switzerland
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Abstract |
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The transfer of lymphocytes into severe combined immunodeficiency (SCID) mice induces a
series of histological changes in the spleen, including the appearance of mature follicular dendritic cells (FDCs). Studies were undertaken to clarify the role of lymphotoxin (LT) in this process. The results show that SCID mice have a small and partially differentiated white pulp containing marginal zone and interdigitating dendritic cells, but lacking FDCs. Transferred spleen
cells can segregate into T and B cell areas shortly after their injection to SCID mice. This ability is dependent on signaling through LT- receptor (LT-
R), since blocking ligand-receptor interaction in recipient SCID mice ablates the capacity of the transferred cells to segregate. A
week after lymphocyte transfer, host-derived FDCs appeared in the reconstituted SCID mice.
This induction of FDCs is dependent on LT-
R signaling by B cells since LT-
/
B cells are
incapable of inducing development of FDCs in SCID mice, even after cotransfer of LT-
+/+ T
cells. Therefore, LT plays at least two discrete roles in splenic organization. First, it appears that
LT induces the differentiation of the white pulp to create sites for lymphocyte segregation. Second, LT expression by B cells drives the maturation of FDCs and the organization of B cell
follicles.
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Introduction |
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The spleen is subdivided into the red and white pulp,
the latter being the lymphoid compartment (1). The
histological structure of the white pulp consists of a cuff of
lymphocytes lining the splenic arterioles, referred to as the
periarteriolar lymphocyte sheath (PALS)1. The PALS is
composed mainly of T cells (1, 2), whereas the B cells form
spheroid-shaped structures named primary follicles that are
located in the periphery of the PALS (composed of naive, recirculating B cells; references 3, 4). Upon immunization, these follicles transform into germinal centers (reactive to T cell-dependent antigen and also called secondary follicles;
reference 5). The boundary region between the white pulp
and the red pulp is called the marginal zone and is populated essentially by specialized subsets of macrophages (metallophilic and marginal zone macrophages) and a nonrecirculating population of IgD B cells (6).
The accessory cells are also segregated within the T and B cell areas in the white pulp; interdigitating dendritic cells, which belong to a hematopoietic lineage (7), are present in the PALS (7), whereas the follicular dendritic cells (FDCs), a cellular lineage of controversial origin (8, 9) are associated with the B cell vollicles. Together with these cellular elements, there are also differences in the distribution of some extracellular matrix proteins that are found in these subanatomic sites. The T cell areas are rich in reticular fibers (10), tenascin (11), and laminin (12), whereas B cell follicles are richer in vitronectin and fibronectin (12, 13).
The cytokines of the TNF/lymphotoxin (LT) family are
important in the establishment and/or maintenance of the
normal splenic architecture as shown by the findings that
the LT- (14), LT-
(15), TNFR-I (16), and TNF-
(17)
knockout mice all have abnormal splenic architecture, as
do mice in which LT-
/
signaling is disrupted (18). It
is not known why defects in signaling by TNF/LT create
such disturbances in splenic architecture. Signaling via the
LT axis between lymphocytes and their microenvironment likely contributes significantly to the organization of the
spleen. In this regard, it is interesting that the FDCs, a conspicuous component of B cell follicles, are not present in
any of the different TNF/LT knockout mice (14).
SCID mice that lack mature T and B lymphocytes also lack
FDCs (21). Interestingly, host-derived FDCs differentiate in the spleen of SCID mice after transfer of wild-type
lymphocytes (21).
Data presented in this report show that SCID mice, devoid of any identifiable FDCs, have a rudimentary white
pulp with marginal zone and areas "predetermined" to be
B cell follicles. The persistence of these predetermined sites
in the SCID mouse is dependent on LT expression. After
the initial colonization of these predetermined areas by B
cells, expression of LT- by the B cells induces the development of mature FDCs. It appears that LT expression
only by B cells, and not T cells, is crucial for the maturation of FDCs and follicles. Therefore, LT plays at least two
discrete roles in splenic organization, an early role involved
with maintaining the differentiation of the splenic stromal
elements, and a later one, where LT-
expression by B
cells and/or by non-T, non-B cell populations drives the
maturation of FDCs.
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Materials and Methods |
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Mice.
BALB/c, BALB/c scid/scid, and C57BL/6 mice were purchased from the National Cancer Institute laboratories (Bethesda, MD). C57BL/6 scid/scid and LT-Transfer of Splenocytes.
In some experiments, whole spleen single cell suspensions were obtained from BALB/c, C57BL/6, or LT-Reagents and Antibodies.
LT-Evaluation of the Splenic Architecture: Analysis Using Viable Thick Sections and Image Analysis.
Spleens were harvested and embedded in 4% agarose in HBSS. The embedded tissue was sectioned in a vibrating microtome (Microcut H12; Energy Beam Sciences, Agawam, MA). The spleen sections (500 µm thick) were incubated overnight at 4°C with the corresponding mAbs conjugated to FITC, biotin, PE, or Cy5, all at a concentration between 10 and 20 µg/ml in PBS/1% BSA/0.02% sodium azide. Mouse IgG1 was used to block Fc binding. After washing, the sections were incubated for 3 h with Streptavidin FITC or Streptavidin PE (Southern Biotechnology Assoc., Birmingham, AL). After washing again, the samples were mounted in slides with PBS/azide/10% glycerol and analyzed on the confocal microscope (BioRad 1024; BioRad Labs., Hercules, CA). This technology offers a number of attractive assets. First, virtually all antibodies that stain by flow cytometry also stain with this method. Second, it appears that the sensitivity of detection may be superior to other standard immunohistological methods. Finally, simultaneous, three-color immunohistological analysis is possible. ![]() |
Results |
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Studies were undertaken to evaluate if T and B cells could segregate in the spleen before the appearance of FDCs. To test this hypothesis, BALB/c SCID mice (devoid of FDCs) were injected intravenously with 1.5-2.5 × 107 syngeneic spleen cells from wild-type donors. The next day, the homing pattern of the infused lymphocytes in the host SCID mice was analyzed by confocal image analysis. Studies were performed through immunohistological analysis of viable, thick sections of the spleens. In contrast to conventional immunohistochemistry, this method is executed without the use of fixatives, and permits greater sensitivity and simultaneous, multicolor analysis. As is shown in Fig. 1 (longitudinal cut of the white pulp) and in Fig. 2 C (transversal cut), the reconstituted SCID mice had a detectable number of CD4+/CD8+ T cells (blue) and CD19+ B cells (green) that segregated in a similar manner to that of wild-type mice. The T cells were concentrated around the arterioles forming the PALS, and the CD19+ B cells appeared to form follicular structures in the periphery of the PALS (Fig. 1 and Fig. 2 C). The transferred lymphocytes which formed follicular structures were B220+, IgD+ phenotype (data not shown). These follicles and PALS (Fig. 1 and Fig. 2 C) were smaller than those from a wild-type BALB/c (Fig. 2 A), which may reflect the limited number of lymphocytes in the reconstituted SCID. As expected, the control, noninjected SCID lacked detectable B and T cells (Fig. 2 B).
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Attempts were made to identify the elements in the white pulp from SCID mice that are involved in guiding the segregation of the transferred T and B lymphocytes. Within the spleen of control SCID mice, the white pulp was delimited by bands of staining for MAdCAM-1 (stains the marginal sinus cells; reference 6; Fig. 2, B and E) and B7.2 (brightly stains the marginal zone macrophages; reference 26; Fig. 2 H).
FDCs, identified by the specific markers FDC-M1 and FDC-M2, were not detected in splenic sections prepared from SCID mice (Fig. 2 K), but were found associated with B cell follicles in wild-type mice (Fig. 2 J). This absence of FDCs in the spleen of SCID mice has been previously reported (21). Using the markers FDC-M1 and FDC-M2, FDCs continued to be absent one day after transfer of wild-type lymphocytes (Fig. 2 L). Therefore, the lack of mature FDCs did not prevent the transferred B cells from organizing into primary IgD+ B cell follicles in the reconstituted SCID (Fig. 1 and Fig. 2 C). Interestingly, such follicles tended to locate in particular areas where the staining for the marginal zone marker MAdCAM-1 was a wide band instead of a narrow rim delimiting the white pulp (Fig. 1 B and 2 C) as indicated by the yellowish color of the B cell follicles (Fig. 1 B and 2 C). It must be noted that a yellow color indicates colocalization in the same area of the green (B cells) and the red (MAdCAM-1) stainings, not discriminating between single and double positive cells at the resolution used. The separate analysis of the patterns of staining for MAdCAM-1 (Fig. 1 C) and CD19 (Fig. 1 D) allowed us to conclude that MAdCAM-1 staining was not present in B lymphocytes.
In contrast to the absence of FDCs, interdigitating dendritic cells (IDCs) identified by the marker CD11c, were detected in SCID mice and located within the area delimited by the marginal zone markers forming a cuff around the central arterioles (Fig. 2, E-I). There was also a rim of CD11c+ cells running by the outside of the marginal zone markers (Fig. 2, E-I). Interestingly, CD11c+ cells (green signal, Fig. 2, D-I) tended to avoid the discrete areas in which the distribution of MAdCAM-1 and B7.2 was a wide band instead of a narrow line (red signal, Fig. 2, D-I). Taken together, IDCs are present in the spleen from nonmanipulated SCID (Fig. 2, E and H) and wild-type mice (Fig. 2, D and G), and concentrate in the periarteriolar area (Fig. 2, D-I).
Blocking of LT-The results presented above show that wild-type lymphocytes transferred into SCID mice segregate into B cell follicles and T cells areas in the absence of mature FDCs. To
evaluate if LT plays any role in creating these predetermined sites, SCID mice were injected with 200 µg of LT-R-Ig or control polyclonal human IgG1. 6 d later, the
SCID mice received 2.5 × 107 wild-type spleen cells intravenously. The following day, the spleens were harvested,
immunostained, and analyzed by confocal microscopy. The
results show (Fig. 3) an absence in CD4+/CD8+ T cell and
CD19+ B cell segregation in the white pulp of the SCID
mice pretreated with LT-
R-Ig (Fig. 3, A and B). In contrast, in the SCID mice treated with the control protein,
there was a normal segregation with B cells organizing follicle-like structures on the periphery of a T cell area (Fig. 3,
C and D). The expression of the marginal zone markers
MAdCAM-1 and B7.2 was downregulated in the SCID
mice treated with LT-
R-Ig (not shown) confirming the
activity of the fusion protein (20). The administration of
another fusion proteins does not affect marginal zone
markers (21).
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To determine if T/B cell segregation was mediated
through LT- expressed on the transferred lymphocytes or
the recipient stroma, the following studies were performed.
Splenic lymphocytes obtained from LT-
/
mice were
used as donor cells for the transfer experiments to SCID
mice. 1 d later, both the LT-
/
and wild-type B and T
cells segregated into follicles and into PALS, respectively
(Fig. 3, B and D). This suggested that LT-
expression on
the donor lymphocytes was not essential for segregation. It
is worth noting that the splenic architecture of the donor LT-
/
mice is very disturbed, lacking marginal zone and
B/T cell segregation. Therefore, these results suggest that
elements of the white pulp that are present in SCID mice
are adequate to direct the normal short-term homing of
LT-
/
cells.
Studies have shown that FDCs develop after lymphocyte transfer into SCID mice (21). In wild-type and in reconstituted SCID mice, FDC-M1 and FDC-M2 expression appear closely associated with CD19+ staining. The origin of the emerging FDCs was also confirmed. Spleen cells from CB6F1 (BALB/c × C57BL/6 F1) were transferred into BALB/c SCID mice and it was observed that the T and B lymphocytes expressed the donor MHC class I haplotype H-2b,d, whereas the FDCs were of host origin (single positive H-2d; data not shown). Thus, spleen cells induced the appearance of host-derived FDCs in SCID mice as has been previously reported (23).
It was next determined whether LT-R-Ig treatment
interferes with the differentiation of FDCs in reconstituted
SCID mice. To this end, SCID mice were coinjected with
2.5 × 107 wild-type spleen cells and 200 µg of LT-
R-Ig.
2 wk later, the spleen sections were stained and analyzed by
confocal microscopy. In reconstituted SCID mice treated
with LT-
R-Ig (Fig. 4, B, D, and F), there was minimal
expression of FDC-M1 and FDC-M2 codistributed with
CD19+ B cells. In addition to the FDC clusters, FDC-M2
stains an unidentified stromal component on the red pulp
of the spleen (27). Furthermore, LT-
R-Ig treatment prevented the B cells from organizing into follicle-like structures and they appeared to concentrate in a "ring" of B
cells around the PALS (Fig. 4, B, D, and F). Cells transferred to control human Ig-treated SCID induced defined
B cell follicles and FDCs (Fig. 4, A, C, and E). Treatment
with OX-40-Ig (not shown) and LFA3-Ig (21) fusion proteins did not affect FDC induction.
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The fact that FDCs
developed in SCID mice after lymphocyte reconstitution
in a LT-dependent fashion suggested that expression of
LT- on the transferred cells induced the appearance of
FDCs. To test this hypothesis, spleen cells or mixtures of T
and B cells that were either from wild-type mice or LT-
/
mice were tested for their capacity to restore splenic
lymphoid organization. Spleen cells from LT-
/
mice
were transferred to C57BL/6 SCID mice, and 2 wk later,
the splenic architecture and presence of FDCs was assessed.
As is shown in Fig. 5, A-C, CD19+ B cells form abnormal
ring-like structures that surround the PALS. With reference to the induction of FDC development, the expression
of FDC-M1 was negative and FDC-M2 was low in the
SCID mice reconstituted with LT-
/
spleen cells (Fig.
5, A and B), in contrast with wild-type reconstituted SCID
(Fig. 5, J and K). The residual staining for FDC-M2 colocalized in the ring-like structures where the CD19+ cells
concentrated. Interestingly, the abnormal splenic architecture of the donor LT-
/
mice does not include these
ring-like structures, but an absence of segregation into B
and T cell areas (data not shown). A population of MAdCAM-1+ cells was situated lining the outside of the rings of
B cells (Fig. 5, C, F, I, and L), which indicates that the
marginal zone is not disturbed as happens in the LT-
R-Ig-treated mice.
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To identify the cell type required for the induction of
FDC development and splenic organization in SCID mice,
cotransfer experiments of LT-/
and/or LT-
+/+ T and
B cells were performed. Cotransfer of T cell-depleted, LT-
/
spleen cells (composed of 80-87% B cells) plus B
cell-depleted LT-
+/+ spleen cells (composed of 75-85%
T cells) showed (Fig. 5, D-F) that the cotransfer of LT-
+/+
T cells did not support the normal organization, e.g., the B cells were in ring-like structures (Fig. 5, D-F) and FDCs
were not differentiated (Fig. 5, D-E). On the contrary,
SCID mice reconstituted with T cell-depleted LT-
+/+
spleen cells plus B cell-depleted LT-
/
spleen cells
showed normal T/B segregation and induction of FDCs (Fig. 5, G-I and Table 1). These experiments suggest that
FDC induction and long-term maintenance of normal
splenic architecture requires LT-
signaling by B cells
and/or by non-T, non-B cell populations. The presence of
LT-
expressing T lymphocytes is not sufficient to induce
FDCs.
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![]() |
Discussion |
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The data presented in this study show that B lymphocytes can segregate from T cells in the absence of mature
FDCs, and B cells induce the appearance of FDCs through
the expression of LT-. Although it has been assumed that
FDCs create a nucleation site for B cell follicle formation,
the data presented suggest that sites for B cell follicle formation exist before the maturation of FDCs. Furthermore, an
intimate interaction of B cells with host-derived FDC precursors induces FDC development. Both of these steps of
splenic organization appear to rely on the function of LT-
.
That is, the disruption of LT-
R signaling in SCID mice appeared to erase the predetermined B cells "sites" destroying the ability of B cells to segregate upon entry into the spleen and prevent splenic organization induced by LT-
-bearing
B cells. A summary of these results is presented in Table 2.
|
Data presented show that B cells (either from LT-+/+
or LT-
/
mice) segregated into follicle-like structures 1 d
after their transfer into SCID mice. It is not known what
specific components in the spleens of SCID mice guided
the segregation of transferred T and B cells. Whatever these
components may be, it is clear that blocking of LT-
function in the SCID mice with LT-
R-Ig destroyed these
sites. SCID mice have a small but partially differentiated white pulp with a marginal zone and periarteriolar area occupied by IDCs. Areas within the SCID spleen that express
higher levels of marginal zone markers (MAdCAM-1) are
avoided by the IDCs. These sites appear to be the areas to
which the transferred B cells segregate. MAdCAM-1 expression in the SCID mice is also destroyed by LT-
-Ig
treatment, as has been shown in wild-type mice (19, 20) or
in LT-
-Ig transgenic mice (18). It must be emphasized that the spleens of SCID mice are devoid of mature FDCs
(21) as judged by the absence of FDC-M1 and FDC-M2 expression, as well as by the absence of immune complex retention (21). In addition, the use of other FDC-specific mAbs (28) have indicated that mature FDCs were
absent in SCID mice (data not shown). It is possible that
FDC precursors present in the spleen of SCID mice
chemoattract or bind B cells (28, 29); although they do not,
as yet, express FDC markers. Alternatively, B cell segregation into follicles after short-term transfer could be mediated through secreted chemokines and/or adherence to extracellular matrix proteins. The fact that B cells from LT-
/
mice segregate into follicular structures implies that
direct LT-
R signaling by B lymphocytes is not necessary
for short-term homing. Furthermore, the fact that homing
of B cells can be disturbed after 1 wk of treatment of recipient SCID mice with LT-
R-Ig suggests that such hypothetical chemokines or extracellular matrix proteins must
have a relatively rapid turnover and/or their secretion is dependent on LT-
R signaling. Taken together, these
findings support the hypothesis that LT-
R-LT-
/
interactions by nonlymphoid cells is necessary to establish the
architecture to permit short-term homing of B lymphocytes.
MAdCAM-1+ cells located in discrete sites of the white
pulp of SCID mice may mark the relevant cell population
important in guiding the selective homing of B cells. Interestingly, the expression of MAdCAM-1 is dependent on
LT- since blocking with LT-
R-Ig or genetic loss of
LT-
(15) eliminates MAdCAM-1 expression and dismantles the integrity of the splenic marginal zone (18). The
functional significance of marginal zone MAdCAM-1 expression (29) in the spleen is unclear. Splenocytes lack overt
expression of the ligand for MAdCAM-1 (
4
7 integrin;
references 30, 31), which is expressed preferentially on
lymphocytes that traffic in the mucosal circuit (Peyer's
patches, intraepithelial lymphocytes, lamina propria lymphocytes; reference 31). Furthermore, the administration of
a blocking anti-MAdCAM-1 mAb does not appear to prevent homing of lymphocytes in a normal spleen, whereas it inhibits the entry into Peyer's patches (29). Therefore, it is
unlikely that MAdCAM-1 is directly responsible for initial B cell segregation. However, experiments aimed to exclude this possibility are underway by testing the ability of
the anti-MAdCAM-1 Ab to interfere with short-term segregation of B cells in SCID mice. Because of the lack of
lymphocytes in the SCID spleen, LT-
expression in nonlymphoid cells (32) or NK cells (32) must be responsible
for maintaining MAdCAM-1 expression. That is surprising since expression of LT-
/
and LT-
3 is described as restricted to activated lymphocytes (33).
Having targeted to sites destined to be B cell follicles,
LT- expression on B cells induces follicular organization
and FDC development. A direct role for B cells in FDC
development has been previously implied by the findings
that FDCs are absent in the lymphoid organs of SCID mice
(21) as well as from mice deprived of B cells (36). It has
also been shown that purified B cells obtained after exhaustive elimination of T cells are sufficient to induce FDCs in
SCID mice (23), although there is a report to the contrary
(21). The fact that FDC development occurs normally ~1
wk after lymphocyte transfer to SCID mice and requires
LT-
R signaling suggests that LT-
expression by B cells
may be critical to induce FDC differentiation. This indeed
appears to be the case since B cells from LT-
/
mice are
incapable of inducing development of FDCs in SCID
mice. The requirement for LT-
expression on B cells was
observed even in the presence of LT-
-expressing T cells
and within a white pulp expressing LT-
.
It has been reported that deficiencies in other cytokines
of the family TNF/LT produce defects in FDC development and splenic B/T cell segregation (14). There is a
loss of splenic follicles in the absence of LT-R signaling
(18) and in TNFRI (16) and TNF (17) knockouts. The
normal follicular organization of B cells in the spleens of
these mice is replaced by a ring-like distribution surrounding the location that would be the marginal zone in a normal spleen. However, the B cells present in the "rings" are
not marginal zone µhigh
B cells (6), but are of the µ+
+
follicular phenotype (17, 19). Therefore, although B cells appear to assemble into follicles shortly after transfer, it appears that in the absence of mature FDCs, B cells ultimately
condense around the PALS to form rings. Interestingly, the
LT-
/
spleen cells transferred to SCID organize in ring-like structures surrounding the PALS 2 wk after transfer.
That is, they organize differently than in the spleen of the
donor LT-
/
mice (14) and in a very similar manner to
the splenic architecture of the LT-
R-treated mice (20).
One explanation for this difference is that the SCID have a
LT-
-expressing splenic stroma that can support a partially
restored splenic architecture. This is consistent with data
reported by Fu et al. (37), which show that after wild-type
LT-
/
splenocyte cross-transfer, the splenic architecture
shows the phenotype of the host. So, wild-type splenocytes
transferred to irradiated LT-
/
mice organize in a nonsegregated structure (37). This supports the hypothesis that
in a wild-type splenic stroma, there are elements dependent
on LT-
signaling that can guide the segregated homing of
B lymphocytes. However, expression of LT-
in the B
cells themselves is necessary for the maturation of normal
primary B cell follicles and FDCs. The LT-
/
mice seem
to have a deeper disturbance in the splenic architecture with absence of segregation between B and T cells and no
clear border between red and white pulp.
In summary, LT- plays a critical function in sculpturing
the architecture of the spleen. First, expression of LT-
by
non-T, non-B cells in spleens of SCID mice induce sites
that can mediate the segregation of mature T and B cells.
Treatment of SCID mice with LT-
R-Ig erases these sites
leading to a loss in T/B cell segregation. Second, LT-
has
to be expressed on B cells to induce FDC differentiation.
Expression of LT-
on T cells appears ineffective at inducing FDC differentiation, leading to the conclusion that a
direct interaction between B cells and FDC precursors, or
alternatively B cells in cooperation with a non-FDC lineage, is essential for FDC development.
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Footnotes |
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Address correspondence to Randolph J. Noelle, Department of Microbiology, Dartmouth Medical School, 1 Medical Center Dr., Lebanon, NH 03756. Phone: 603-650-7670; Fax: 603-650-6223; E-mail: rjn{at}dartmouth.edu
Received for publication 19 November 1997 and in revised form 6 January 1998.
1Abbreviations used in this paper: CD, cluster of differentiation; FDC, follicular dendritic cell; IDC, interdigitating dendritic cell; LT, lymphotoxin; PALS, periarteriolar lymphocyte sheath. ![]() |
References |
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