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Departments of
*
Microbiology and Immunology and
Anatomy, Division of Immunobiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298;
Stanford University, Palo Alto, CA 94305;
§
Basel Institute for Immunology, Basel, Switzerland; and
¶
The Jackson Laboratory, Bar Harbor, ME 04609.
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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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In our laboratories, we have confirmed these results (Kosco et al., unpublished observations). However, in both studies, what appears now to be an essential component of the experiments failed to occur. FDC are radioresistant and are not eliminated by doses of irradiation that even exceed 1200 R (e.g., 1600 rad (Burton, unpublished); 18.5 Gy (9)). Clearly, the lymphocytes and macrophages are eliminated by these doses, but Ag-trapping FDC are still present in the lymph nodes. Thus, it may be argued that host FDC were not eliminated from the recipients by irradiation, and the persisting FDC and FDC precursors may have inhibited donor FDC from emerging in the chimeric mice.
Data do exist to support the concept that FDC are derived from cells
coming into the lymphoid follicles from a distal site. Ag-transporting
cells (ATC) have been identified that trap immune complexes in the
lymph and move these complexes into the follicles of draining lymph
nodes on the extracellular surface of their plasma membranes (10).
These ATC are reactive with the mAb produced against FDC (FDC-M1) (11),
bind immune complexes, and have morphologic features in common with FDC
(1). These features prompted the hypothesis that ATC may be the FDC
precursors. In addition, Parwaresch et al. (12) demonstrated that the
mAb KiM4, which is specific for human FDC, reacts with a mononuclear
cell in the blood. These authors suggested that KiM4+
mononuclear cells are possibly also circulating precursors of FDC. The
fact that the mAb KiM4 was raised originally against a purified
fraction of U-937, a macrophage-like cell line, raises the possibility
that FDC may be of hemopoietic origin. This is also consistent with the
antigenic phenotype of FDC that has been reported to bear cell surface
markers in common with leukocytes, including: common leukocyte Ag,
intercellular adhesion molecule-1, class II, CR1, CR2, Fc receptors
(both Fc
RII and Fc
RII), and CD40 (1).
Severe combined immunodeficiency (prkdcscid) mice, hereafter termed SCID mice, lack functional B and T cells (13) and have been shown to also lack FDC (14). As such, the SCID mouse appears to provide an optimal system to study the origin of FDC, since the problem of eliminating radioresistant mature FDC could be bypassed. Using the SCID mouse model, the objective of the present study was to determine whether primary lymphoid tissues contained FDC precursors. We report in this work that FDC of the donor phenotype can be found in SCID mice after reconstitution with primary lymphoid tissue from either mice or rats. These data indicate that FDC can be derived from precursors in primary lymphoid tissues that migrate into secondary lymphoid tissues, and these results raise questions about FDC being derived from local stromal cells in the secondary lymphoid tissue.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pregnant females (for newborn mice) or 6- to 8-wk-old homozygous mutant C.B-17-scid/scid (H-2d, SCID), C57BL/6J-scid/scid (H-2b, SCID), and F1 (BALB/cBy x C57BL/6J) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Lewis rats (6–8 wk old) and pregnant Lewis rats (day 16 gestation) were purchased from Harlan Laboratories (Indianapolis, IN). ROSA BL/6 F1 (H-2b) were a generous gift of Herzenberg Laboratory at Stanford University (Palo Alto, CA). The animals were housed in a specific pathogen-free environment and given food and water ad libitum.
Cell transfers for reconstitution
Before cell transfer, C.B-17-SCID mice were irradiated with 300 rad to facilitate reconstitution (15). Bone marrow cells were obtained from femurs and tibias of F1 mice, ROSA BL/6 F1 mice, and Lewis rats. Rat fetal liver cells were obtained by homogenizing the fetal livers between frosted ends of glass slides. For reconstitutions, 6- to 8-wk-old SCID mice received i.v. 2 x 107 murine bone marrow or 5 x 107 rat fetal liver cells suspended in 200 µl of HBSS supplemented with HEPES (25 mM) and gentamicin (50 µg/ml). Newborn C.B-17-SCID mice received 107 rat bone marrow or rat fetal liver cells i.p. Newborn C57BL/6J-SCID mice received 5 x 106 ROSA BL/6 F1 bone marrow cells i.p.
Immunizations
Mice received an initial 0.1 ml injection consisting of 200 µg/ml alum-precipitated human serum albumin (fraction V; Sigma Chemical Co., St. Louis, MO) plus 5 x 108 heat-killed Bordetella pertussis s.c. behind the neck. Two to ten weeks later, the mice were given a booster immunization (0.05 ml) on the dorsum of each footpad with the same immunogen. Lymph nodes and spleens were obtained from these mice 5 days after the secondary challenge.
Immunohistochemistry
The mouse anti-rat FDC-specific mAb ED5 (17) (a generous gift from Dr. C. D. Dijkstra, Free University, Amsterdam, The Netherlands) was used to detect rat FDC. Mouse FDC were detected by unconjugated or biotinylated rat anti-mouse FDC-reactive mAb, FDC-M1 (11). Biotinylated anti-H-2Kb and anti-H-2Kd mAbs were obtained from PharMingen San Diego, CA. The following second-step reagents were used: fluorescein-conjugated rat anti-mouse F(ab')2 IgG (H+L), mouse anti-rat F(ab')2 IgG (H+L) (Jackson ImmunoResearch Laboratories, West Grove, PA), streptavidin-FITC, and streptavidin-Texas Red (Southern Biotechnology, Birmingham, AL). Lymph nodes and spleens from reconstituted SCID mice were immediately embedded in Tissue Tek II OCT compound and frozen on dry ice. Frozen sections were then cut at a 6- to 8-µm thickness and mounted onto poly(L-lysine)-coated slides. After fixing in cold acetone for 30 s and air drying for 1 h, immunohistochemistry was performed by incubating these sections with different primary Abs in PBS with 1% BSA for 2 h at room temperature. The sections from F1 bone marrow reconstituted SCID mice were incubated simultaneously with anti-MHC class I Abs and FDC-M1. The sections were washed three times in PBS over a period of 15 min and incubated in optimal dilutions of secondary reagents for 1 h at ambient temperature. The sections were then washed, mounted, examined by fluorescence microscopy, and photographed. Controls included sections incubated with only second-step reagents or with inappropriate Abs of the same isotype, and were negative.
Isolation of FDC
The procedure developed by Schnizlein et al. (18) and modified by Kosco et al. (11, 19) was used to isolate FDC. The low density, nonadherent cell fraction was obtained from enzymatically digested lymph nodes of immune mice 2 days after whole body irradiation (600 rad; cesium source). The gentle isolation procedure is essential for isolating FDC, and radiation treatment is important to isolate FDC with far fewer contaminating lymphocytes. The association of B cells intertwined within the FDC dendritic processes makes standard depletion techniques difficult (19). In brief, the draining lymph nodes from immunized mice were placed in small tissue culture plates containing an enzyme mixture of collagenase (2.5 mg/ml; CLS 4, number 4188; Worthington, Biochemical Corp., Freehold, NJ) and deoxyribonuclease I (1%/ml; DN25; Sigma Chemical Co.) in 2 ml HBSS. Each lymph node capsule was opened using two 26-gauge needles, and the preparation was placed in an incubator at 37°C, 5% CO2. After 20 to 30 min, the partially digested stroma was gently pipetted. The released cells within the supernatants were then collected in tubes containing HBSS plus 5% FCS and placed on ice. A fresh aliquot of enzyme mixture was then added to the remaining tissues and returned to the incubator. After another 30 min, the tissue was again pipetted, this time to the point that nearly all of the cells were released from the stroma. The few remaining large pieces of tissue were discarded, and all supernatant fluids were pooled. The cells were then washed by centrifugation in HBSS and resuspended to 1 to 2 x 108 cells/ml, and 2 ml was layered over each continuous Percoll gradient. The gradients were then centrifuged at 400 x g for 30 min, and the 1.060 to 1.065 g/ml low density band was removed. After washing this fraction two or three times in HBSS, the cells were resuspended in complete medium (HBSS plus 10% FCS, penicillin/streptomycin, and 2-ME). The suspension was placed in a small tissue culture dish (Costar, 3035, Cambridge, MA) and incubated at 37°C for 1 h to deplete adherent populations.
Flow cytometric analysis
To elucidate the expression of lacZ, the FDC-enriched cell preparation was stained with a fluorogenic substrate for ß-galactosidase, fluorescein-di-ß-D-galactopyranoside (FDG) (Molecular Probes, Eugene, OR), as described in detail elsewhere (20). Briefly, cells were loaded with FDG substrate by a hypotonic shock at 37°C for 1 min. FDC were identified by incubating the cells with biotinylated rat anti-mouse FDC-reactive mAb, FDC-M1, followed by washing and incubation with streptavidin-phycoerythrin (PE) (Southern Biotechnology). FDC-enriched cell preparations from BALB/cBy mice served as a negative control for lacZ expression. Cells (1 x 104) were analyzed on a FACScan (Becton Dickinson, San Jose, CA) flow cytometer. Dead cells were excluded from analysis using propidium iodide uptake.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four to six months after transferring F1 bone
marrow cells into adult SCID mice, spleen and lymph nodes were
harvested, sectioned, and analyzed for FDC of both the donor and host
phenotype. In many follicles of the F1 bone marrow
reconstituted SCID mice, it appeared that FDC expressed only the host
class I molecules in germinal centers (Fig. 1
f). However, in other
follicles, numerous FDC bore donor class I molecules, as indicated by
double labeling for donor class I and FDC-M1 (Fig. 1c).
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Confirmation of FDC precursors in murine bone marrow was obtained
using the lacZ mouse model. ROSA BL/6 F1 mice
transfected with the lacZ gene express the gene product,
ß-galactosidase, in all cells (16). Through the action of this gene
product, the fluoresceinated substrate, FDG (20), is cleaved and
fluorescein is released into the cytoplasm. As a result, the cell
becomes fluorescent and detectable by flow cytometry. Using the same
protocol for the construction of chimeras as above, newborn SCID mice
received bone marrow cell transfers from ROSA BL/6 F1 mice.
We reasoned that if SCID mice received ROSA BL/6 F1-derived
bone marrow FDC precursors, then donor FDC could be identified by the
presence of the lacZ gene product. Newborn mice were chosen
to minimize the potential for host FDC precursors to establish
themselves before the donor FDC precursors. As indicated in Figure 2D, more than one-half of the
FDC-M1+ cells obtained from these chimeric mice also
labeled with FDG, indicating the presence of the lacZ gene
product representing donor-derived FDC. Incubating these preparations
without the fluoresceinated substrate or streptavidin-PE provided the
background level of labeling (Fig. 2A). An
FDC-enriched preparation obtained from normal BALB/cBy mice treated
with the FDC-M1 mAb and the fluoresceinated substrate (Fig. 2B) is included for comparison, and finally, the
FDC-enriched preparation from chimeric mice incubated without the
FDC-M1 mAb is shown in Figure 2C.
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, a–h, confirmed the
presence of the lacZ gene product in cells with FDC
morphology. FDC isolated from BALB/cBy control mice did not show green
fluorescence (control; data not shown).
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Both donor and host FDC appear to develop in the recipients of a
murine bone marrow transfer. The mAb FDC-M1 does not distinguish
between donor vs host FDC. We therefore sought to confirm the presence
of donor FDC using a second system in which the mAb will only label
donor FDC. SCID mice can be reconstituted with rat cells (21). We
therefore reconstituted newborn SCID mice with bone marrow or fetal
liver cells derived from rats, and 4 to 6 mo later, spleen and lymph
nodes were analyzed for the presence of FDC of either rat
(ED5-positive) or murine (FDC-M1-positive) origin. Of seven rat bone
marrow reconstituted SCID mice, three mice clearly showed the presence
of ED5+ FDC networks in lymph nodes and spleens (Fig. 4, a and c).
Similarly, one of five recipients of rat fetal liver contained rat FDC
in their lymphoid organs (Fig. 4f). We also noted
that a given follicle tended to have either rat- or mouse-derived FDC
predominating, although there were follicles with both cell types
(Figs. 4, d and g). It should be noted
that FDC-M1+ cells were not reactive with ED5, indicating
that the mAb ED5, as reported (17), does not cross-react with mouse
FDC. Similarly, the ED5+ cells did not cross-react with the
mAb FDC-M1 (Fig. 4, c and d). Clearly,
reconstituting mice with rat bone marrow or fetal liver was sufficient
to elicit the maturation of murine FDC in both the lymph nodes and the
spleens (Figs. 4, d and g). In some rat
bone marrow or fetal liver reconstituted SCID mice that lacked rat FDC,
it appears that the rat cells had simply not engrafted. In others,
there were sites in which a few ED5-positive cells appeared to be
present in follicles, but the typical large FDC reticulum was not
apparent and the animals were scored as negative.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The radioresistant nature of FDC makes it difficult to eliminate these
cells, and it is possible that in radiation chimeras, the persistence
of host FDC reported in previous studies (8) inhibited or markedly
diluted the donor source of FDC in the tissue. It should be noted that
FDC bear immunogen for many months to years, suggesting that the FDC
are not turning over, and thus, FDC in secondary lymphoid tissue might
be expected to persist for months to years (1). SCID mice lack FDC
(14), and therefore, the problem of eliminating host FDC at the outset
can be bypassed. Recently, we showed that transferring B and T cells
can induce host FDC development in SCID mice, suggesting the presence
of FDC precursors in these mice (14). The fact that rat bone marrow
cells would support the development of murine FDC, noted in the present
study, further supports the concept that FDC precursors are present in
SCID mice. Previous reports showed that FDC are first found in lymphoid
tissues at about 3 wk after birth (2, 4, 22). We reasoned that pre-FDC
may migrate from the bone marrow and may be dispersed in tissues
throughout the body. We also believe that these dispersed precursors
play an important role in Ag transport and repopulation of FDC networks
in recipients, whether these are SCID mice or radiation chimeras. Thus,
even if FDC precursors in the bone marrow are less radioresistant than
mature FDC, the pool of intermediate-type pre-FDC could be large enough
to supply precursors for months, resulting in the development of new
FDC networks. By injecting the donor bone marrow cells containing FDC
precursors into newborn SCID mice, we sought to minimize the
competition from host FDC and their precursors. The injected donor bone
marrow cells are known to home to the host bone marrow (23), and we
reason that both donor and host FDC precursor cells are dispersed to
various connective tissue compartments via the blood. The mobilization
stimulus for these donor and host pre-FDC (ATC) (10) may be a cytokine
or a lymphokine, as suggested by the B and T cell requirements for FDC
development (14). The absence of FDC networks in
TNF-
-/- (24) or LT--/- (25) mice
suggests these lymphokines may play a role in FDC development. The
formation of immune complexes that bind the pre-FDC may lead to the
migration of donor and host ATC into the draining lymph nodes. Thus,
the presence of both donor and host FDC in the lymph nodes and spleen
of reconstituted newborn SCID mice might be predicted.
Recently, Yoshida et al. (26) showed the presence of host FDC in the
spleen of SCID mice after transferring allogeneic lymphocytes. This is
in agreement with our data showing the development of mouse FDC in SCID
mice reconstituted with rat bone marrow and fetal liver cells. It
appears that FDC precursors in SCID mice can develop in presence of
syngeneic, allogeneic, or even xenogeneic lymphocytes, as shown in this
study. Additionally, they also noted the presence of FDC-M1-positive
cells that did not appear to express the host phenotype. These authors
indicate that FDC-M1 reacts with two FDC populations of different
origin (26). It is possible that heterogenous populations of FDC may
have different origin. However, since they used 6-wk-old SCID mice, in
contrast to newborn SCID mice, for reconstitution and splenic cells
enriched for B lymphocytes in contrast to bone marrow cells, it may
have minimized the development of FDC of donor origin in their study.
Moreover, these authors examined the spleens 5 to 6 wk after
reconstitution in contrast to 3 to 6 mo in most of our experiments. We
believe that due to slow turnover of FDC (1), long-term reconstitution
(3–6 mo) allows time for donor precursors to be recruited in the
formation of FDC networks. This time frame contrasts with our previous
study, in which FDC were found 2 to 3 wk after reconstitution with B
and T cells (14). We reason that numerous FDC precursors are present in
adult SCID mice, and that they only require lymphocyte stimulation to
complete development. In the present study, we deliberately used
newborn SCID mice so that both donor and recipient precursors are at an
early stage of development, and we tried to inject enough bone marrow
cells so that the number of host FDC precursors did not overwhelm the
small number of donor FDC precursors injected. The presence of similar
numbers of host and donor FDC in the adult mice suggests that we were
successful (Fig. 2
).
In previous studies, a one-to-one relationship between the number of
follicles trapping immune complex and the number of germinal centers
that subsequently developed was described (27, 28). This suggests the
Ag-bearing FDC elicited the germinal center and that the FDC is
critical to the process. The fact that TNF--/- (24)
and LT--/- (25) mice lack FDC and also lack germinal
centers further supports the concept that FDC are critical to the
process of normal germinal center development. Interestingly,
Cr2-/- mice also lack normal germinal center development
(29), and this may also relate to a deficit in FDC-B cell
communication. FDC bear immune complexes and C3 fragments that are
known ligands for CR2, and this prompted the hypothesis that CR2 ligand
on the FDC binds CR2 receptor on the B cell (30). Recent data from our
laboratory support this hypothesis and indicate that Ab responses are
depressed dramatically when FDC-B cell communication via CR2 ligand/CR2
is blocked (Qin et al., unpublished).
The chief issue raised and unresolved by the present study is whether bone marrow FDC precursors are derived from hemopoietic cells or stromal cells. Experiments are underway in which we are looking at SCID mice reconstituted with various kinds of bone marrow cells, including leukocyte precursors. In preliminary studies, we have identified cells in the bone marrow reacting with the mouse FDC mAb FDC-M1, and these cells are also reactive with F4/80. It is possible that the F4/80-FDC-M1 reactivity may be a coincidence or a true indication of a hemopoietic/myeloid lineage for FDC. The fact that Parwaresch et al. (12) demonstrated that the FDC-specific mAb KiM4 reacts with a mononuclear cell in human blood, together with the fact that the mAb was originally raised against the U-937 cell line, which is closely related to monocytes, further suggests the idea that FDC may be of a hemopoietic/myeloid lineage.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Zoher F. Kapasi, Emory University School of Medicine, Department of Rehabilitation Medicine, Division of Physical Therapy, 1441 Clifton Road, N.E., Atlanta, GA 30322.
3 Current address: 405 Stellar-Chance Laboratories, Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
4 Current address: Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development S.A., 14, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
5 Abbreviations used in this paper: FDC, follicular dendritic cell; ATC, antigen-transporting cell; FDG, fluorescein-di-ß-D-galactopyranoside; PE, phycoerythrin; H+L, heavy plus light chain.
Received for publication July 2, 1997. Accepted for publication October 10, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient mice: a critical requirement for TNF in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184:1397.-deficient mice. Nature 382:462.[Medline]
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