By
From the * Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW, Australia 2050;
the Medical Foundation of the University of Sydney, Sydney, NSW, Australia 2050; and the § Department of Microbiology and Immunology, University of California at San Francisco,
San Francisco, California 94143
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Abstract |
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Secondary lymphoid tissue organogenesis requires tumor necrosis factor (TNF) and lymphotoxin (LT
). The role of TNF in B cell positioning and formation of follicular structure was
studied by comparing the location of newly produced naive recirculating and antigen-stimulated B cells in TNF
/
and TNF/LT
/
mice. By creating radiation bone marrow chimeras
from wild-type and TNF
/
mice, formation of normal splenic B cell follicles was shown to
depend on TNF production by radiation-sensitive cells of hemopoietic origin. Reciprocal
adoptive transfers of mature B cells between wild-type and knockout mice indicated that normal follicular tropism of recirculating naive B cells occurs independently of TNF derived from
the recipient spleen. Moreover, soluble TNF receptor-IgG fusion protein administered in vivo
failed to prevent B cell localization to the follicle or the germinal center reaction. Normal T
zone tropism was observed when antigen-stimulated B cells were transferred into TNF
/
recipients, but not into TNF/LT
/
recipients. This result appeared to account for the defect
in isotype switching observed in intact TNF/LT
/
mice because TNF/LT
/
B cells,
when stimulated in vitro, switched isotypes normally. Thus, TNF is necessary for creating the
permissive environment for B cell movement and function, but is not itself responsible for
these processes.
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Introduction |
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he arrangement of lymphocytes into T and B cell zones within secondary lymphoid tissue is designed to optimize interactions between these cells (1). Of particular importance for the shaping of the B cell repertoire are the events that occur at the interface between the two zones, which involve three types of B cells. The first comprises newly generated B cells derived from the bone marrow competing for selection into the recirculating pool. Although the mechanism remains uncertain, this point of selection is critical because the number of such B cells exceeds the number required to maintain homeostasis of the recirculating repertoire (2). The second consists of mature naive B cells recirculating through follicles. Third, B cells stimulated by antigen above a critical concentration threshold undergo arrest in the outer periarteriolar lymphoid sheath (PALS)1 (the T zone), where the chance of cognate T cell help is optimal (5, 6). If T cell help is provided, the B cells differentiate into antibody-forming cells, which aggregate within extrafollicular proliferative foci, and intrafollicular germinal centers (GCs [5, 7]). Conversely, should T cell help be absent, as occurs in the case of self-reactive B cells, they die in the outer PALS, leading to tolerance (8, 9).
Mice lacking both membrane-bound and soluble lymphotoxin (LT) exhibit marked disorganization of the
splenic white pulp, and fail to form either LNs or Peyer's
patches (10, 11). An even more striking defect has been
observed in the spleens from mice with combined deficiencies of TNF and LT
in which virtually no microarchitectural B or T cell aggregation takes place (12, 13). By contrast, LNs do develop in TNF
/
and TNFR-1
/
(p55)
mice, but the microarchitecture of their LNs and splenic white pulp is abnormal (13, 14). Members of the TNF and
TNFR families also contribute to the events underlying
antigen-induced B cell activation and differentiation. Thus,
splenic GCs fail to develop in mice lacking either LT
,
LT
, TNF, or TNFR-1 (13). Although TNF and LT
are critical for normal lymphoid organogenesis, the mechanism whereby they signal the specific migration of lymphocyte subsets remains uncertain. In this paper, the role of
TNF compared with LT in regulating movement and positioning of naive and antigen-activated B cells has been investigated in a unique set of inbred C57BL/6-TNF
/
and
TNF/LT
/
mice. The results indicate that TNF derived
from a hemopoietic precursor plays a crucial role in development of splenic white pulp, including the T-B interface,
but is not itself responsible for correct B cell movement and
function within the follicle.
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Materials and Methods |
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Mice.
TNFAntibodies and Reagents.
The following reagents were usedAnimal Manipulations.
B cells were prepared, 5-(and -6-)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled, and transferred as described previously (5). For induction of T cell- dependent B cell responses in vivo, mice were immunized with 200 µl i.p. of SRBC (10% vol/vol; provided by Dr. D. Emory, Commonwealth Scientific and Industrial Research Organization, Sydney, Australia). Radiation bone marrow chimeras were generated as described previously (26). In brief, 2 × 107 bone marrow cells from C57BL/6-TNFImmunohistology.
Fluorescence immunohistology and immunocytochemistry were performed on frozen sections, as described previously (5). Immunohistochemistry double staining was developed using alkaline phosphatase substrate (BCIP/NBT) followed by the horseradish peroxidase substrate DAB. After the final wash, slides were mounted and examined by standard bright-field or epifluorescence microscopy (Leitz DMR BE; Leica AG, St. Gallen, Switzerland).Flow Cytometry.
Cells were maintained on ice throughout all labeling procedures. 2-5 × 105 aliquots of cells were examined by flow cytometry using a FACScan® (Becton Dickinson, San Jose, CA). Data were analyzed with CellQuest software.B Cell Proliferation and Ig Production In Vitro.
Small dense B cells were prepared from mouse spleen as described previously (27) except for the additional use of anti-CD8 (31M) in T cell depletion. B cells (5 × 105/ml) were incubated in 100 µl B cell medium (RPMI 1640 supplemented with 10% FCS [Trace Biosciences Pty. Ltd., Castle Hill, NSW, Australia]) and combinations of T cell membrane (27), recombinant IL-4, membrane from baculovirus-infected Sf 9 cells expressing mouse CD40L (baculo-CD40L [28]), LPS (Salmonella typhosa; Sigma Chemical Co.), and mitogenic anti-IgM (b7.6) and anti-IgD (1.19). Cultures were incubated for 3 d, then pulsed with [3H]thymidine (ICN Biomedicals, Inc., Costa Mesa, CA) for 4 h before harvesting and measurement of proliferation by scintillation counting. Triplicate cultures containing baculo-CD40L and IL-4 were incubated for 7 d before supernatant was harvested for measurement of total IgM, IgG1, or IgE by ELISA. ![]() |
Results and Discussion |
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Data from our own
and other groups point to a role for TNF (and LT) in establishment of B cell follicles. In TNF
/
mice, B cells are
arranged in rim-like structures around the T cell aggregates, and segregation of red and white pulp as well as the
interface between T and B cell zones is poorly preserved (13, 14; Fig. 1, A-D). In TNF/LT
/
mice, the lymphoid aggregates (white pulp) are poorly organized, diminished in size, and overlapping so that clear demarcation between T and B cell zones is lost and there is a relative
increase in proportion of lymphocytes within the red pulp
(references 12, 13, and data not shown). To clarify the role
of TNF in these changes, bone marrow chimeras were created by reconstituting WT animals with TNF
/
bone
marrow and vice versa. The white pulp morphology of
WT recipients of TNF
/
bone marrow (Fig. 1, E and F)
had acquired the features of TNF
/
mice, including a loss
of distinct follicles and a blurred T-B cell interface. By
contrast, the TNF
/
recipients of WT bone marrow (Fig.
1, H and I) resembled WT mice. A cohort of bone marrow
chimeras were immunized with SRBC. Spleens from these
mice revealed well-defined PNA+ GCs within the follicles
of TNF
/
recipients of WT bone marrow (Fig. 1 J),
whereas most B cell aggregates in TNF
/
WT bone
marrow chimeras showed no evidence of GC formation
(Fig. 1 G).
|
Thus, TNF derived predominantly from hemopoietic
precursors rather than radiation-resistant stromal elements
is needed for the development of a normal white pulp capable of supporting subsequent antigen-dependent events
within it, including GC formation. Experiments with LT/
bone marrow have yielded comparable results (29). Interestingly, the LT
/
WT bone marrow reconstitution
was shown to result in the loss of follicular dendritic cells
(FDCs) and GCs but preservation of the demarcation between T and B cell zones (29), which points to an exclusive role for TNF in this latter feature of splenic organization. The results reported here complement the work of Tkachuk et al. (30) in TNFR-1
/
chimeric mice, indicating a requirement for TNFR-1 expression on nonhemopoietic cells in maintenance of splenic architecture and
B cell location.
There are two explanations for the dependence of GC formation on TNFR-1 ligation. First TNFR-1 ligation may
be required during the cellular interactions after exposure
to antigen. Alternatively, it may act during organogenesis
to create a permissive environment for later development
of GC reactions. To distinguish between these two possibilities, WT mice were immunized with SRBC (day 0)
and treated with TNFR-Ig (which binds TNF and soluble
LT3 [22]) on three occasions from day 2 after immunization until 1 d before killing and analysis of GC development. Despite TNF blockade in treated mice, GC
reactions had developed normally on day 7 and were indistinguishable from those observed in WT mice treated with
PBS (data not shown, but see also reference 25). Furthermore, GCs in the spleens of both types of mice contained
organized clusters of FDCs (data not shown). Therefore,
TNF-mediated interactions act during development of lymphoid structure to create a milieu wherein GC reactions
can then proceed, rather than being involved in the cellular
interactions responsible for GC formation per se. One caveat is that TNFR-Ig may not completely block the
TNFR-1 signals necessary for GC formation in vivo. However, our own and others' experience argues against this
possibility (see Materials and Methods).
Mature recirculating B cells rapidly enter the follicles
after adoptive transfer into nonirradiated WT mice (5, 6). To determine whether the absence of TNF or TNF/LT
perturbs this process, mature naive splenic B cells from WT
or TNF
/
donors were labeled with CFSE and transferred
into either WT, TNF
/
, or TNF/LT
/
recipients.
The vast majority of WT donor cells were located within
WT follicles 24 h after transfer (Fig. 2 A). By contrast, follicular homing was compromised particularly in TNF/
LT
/
recipients, presumably due to disruption of architecture of the follicle (Fig. 2 C). In TNF
/
recipients, B
cells from either WT or TNF
/
donors were largely located in the vicinity of the follicles which were better preserved than in mice lacking both cytokine genes (Fig. 2, B
and D). When the experiment was reversed and B cells
from either TNF
/
or TNF/LT
/
donors were transferred into WT recipients, precise B cell migration to the
follicles was observed (Fig. 2, E and F).
|
These results suggest that TNF plays a role in generation of normal white pulp but does not directly influence homing of naive B cells. To explore this further, naive B cell migration was examined after administration of TNFR-Ig. On this occasion, anti-HEL Ig Tg mice were used as donors, enabling tracking of B cells by virtue of HEL binding to the transgene-encoded surface Ig (follicular tropism of naive Ig Tg B cells was shown previously to be identical to that of non-Tg B cells [5]). WT recipients were injected with either 200 µg i.v. TNFR-Ig or PBS 4 h before Ig Tg B cell transfer. 20 h later, the distribution of HEL-binding B cells in both TNFR-Ig-treated recipients and PBS-treated controls was identical (Fig. 2, G and H), demonstrating precise localization to the B cell follicles consistent with findings obtained in previous transfer experiments.
Expression of the BLR1 Chemokine Receptor Is Maintained in the Absence of TNF and LTOnce the follicles were
established, B cell follicular tropism did not require TNF
(Fig. 2 D) or LT3 (Fig. 2, G and H). This made good
sense, particularly given the ubiquitous expression of TNF
and the need for a highly focused mechanism to direct intrafollicular B cell traffic. Nevertheless, the necessity for
TNF in the recipient follicle suggested that B cell follicular
tropism is mediated by a TNF-dependent factor. One attractive candidate was the chemokine receptor BLR1 because it is expressed on naive but not activated B cells (31)
and the splenic white pulp of BLR1
/
mice resembles
that of TNF
/
and TNFR-1
/
mice (31). Moreover,
splenic follicular tropism of recirculating BLR1
/
B cells
was shown to be perturbed, whereas migration of WT B cells into the B cell zones of BLR1
/
recipients was normal. To examine the role of BLR1, spleen cells were obtained from WT, TNF
/
, and TNF/LT
/
mice, and
BLR1 expression was assessed by flow cytometry. Dual staining of WT spleen cells for a range of phenotype markers revealed that 95% of B220+ cells expressed BLR1,
whereas <3% of CD4+, CD8+, or Mac-1+ cells were positive (data not shown). When BLR1 expression on WT
B220 cells was compared with that on the same cells from
TNF
/
or TNF/LT
/
mice, not only were levels
maintained in the absence of TNF and LT
, but they also
showed a consistent albeit small increase above the control
(Fig. 3). Thus, although a role for BLR1 in mediating the
effects of TNF (and LT) on primary B cell follicular structure was excluded, the increase in level of expression is
consistent with reduced receptor internalization, possibly
secondary to a deficit in its recently described ligand, BLC
(32).
|
To follow the physiological migration of B cells to the T zone after antigen ligation of the B cell antigen receptor (5, 8), HEL-specific Ig
Tg B cells (TNF and LT-positive) were stimulated in
vitro with 100 ng/ml HEL, and then injected into WT,
TNF
/
, or TNF/LT
/
recipients, where they were
detected in the spleen using HEL-specific antiserum. In
WT mice, B cells migrated to the outer PALS, where they
remained for at least 24 h (Fig. 4 A). Similarly, when activated Ig Tg B cells were transferred into TNF
/
recipients, they arrested precisely in the outer PALS (Fig. 4 B).
However, antigenic stimulation had no apparent influence
on the migration pattern of B cells transferred into TNF/
LT
/
recipients. Thus, B cells were distributed randomly throughout the red and white pulp of the recipients
(Fig. 4 C), as had been observed previously after transfer of
naive B cells into TNF/LT
/
recipients (Fig. 2 C).
|
T cell-dependent B cell responses are
grossly impaired in TNF/LT/
mice, whereas only some
aspects are deficient in the absence of TNF (13, 14). To investigate the possibility that the absence of TNF and/or LT
from B cells prevents B cell proliferation and differentiation,
purified small resting B cells were prepared from the spleens
of both TNF
/
and TNF/LT
/
mice and stimulated in
vitro using protocols that reproduce T cell-dependent and
-independent activation. Stimulation with either activated
T cell membranes or recombinant CD40L resulted in comparable proliferation of B cells irrespective of whether they
were obtained from TNF
/
, TNF/LT
/
, or WT mice.
In each case, proliferation was enhanced by the addition of
IL-4 (Fig. 5 A). Similarly, production of IgM, IgG1, and
IgE by B cells from both mutant strains was normal in the presence of IL-4 (Fig. 5 B). T cell-independent B cell activation with anti-IgM, anti-IgD, or LPS was also unaffected
by either mutation (data not shown).
|
The preceding experiments indicate that the failure of
isotype switching in TNF/LT/
mice is due to loss of T
zone tropism by antigen-stimulated B cells in these mice
(Fig. 4 C) rather than to an intrinsic defect in the switching
mechanism imposed by the absence of these cytokines (Fig.
5). In contrast, the initial phase of the T cell-dependent response to antigen is normal in TNF
/
mice, even though
GCs do not develop. The most likely explanation for this is
the absence of an organized network of FDCs within the B
cell areas. FDC networks have been reported to be absent not only from TNF
/
(13, 14), TNF/LT
/
(12, 13),
and TNFR-1
/
(15, 16, 30) mice but also from LT
/
mice (16). On the other hand, TNF does not appear to be
essential for production of FDCs per se, since TNF
/
mice contain isolated FDCs (13). Interestingly, the source of LT
required for formation of FDC networks has been
shown to be the B cell itself, not the T cell (33, 34). Collectively, these findings raise the question of the respective
roles played by TNF and LT
in formation of FDC networks and subsequently GC reactions. One possible scenario is that TNF secreted by a cell of hemopoietic origin
interacts with TNFR-1+ nonhemopoietic cells, leading to
release of the chemokine BLC. This chemokine could then
bind to BLR1 on adjacent B cells, leading to both formation of structurally correct follicles (permissive for FDC
clustering) and induction of LT expression on B cells, which in turn would facilitate development of FDC networks. The chimera experiments reported here support
such a scenario. When LT
was available but TNF was not
(TNF
/
WT), the extent of the GC reaction was significantly impaired compared with that seen in the presence
of TNF (WT
TNF
/
). That is, the environment was
not permissive for FDC clustering because it had been
formed in the absence of TNF. By contrast, after immunization, GCs developed normally after administration of
TNFR-Ig to (TNF+/+) WT mice with structurally permissive B cell follicles. TNFR-Ig inhibits the activity of soluble LT
3 as well as TNF (22), but the functionally important form of B cell-produced LT for FDC clustering
appears to be the membrane-bound LT
1
2 heterotrimer (33), which would have escaped neutralization by TNFR-Ig. Consistent with this is the absence of splenic GCs in
LT
/
mice (17) despite secretion of soluble LT
3.
![]() |
Footnotes |
---|
Address correspondence to Antony Basten or Jonathon D. Sedgwick, Centenary Institute of Cancer Medicine and Cell Biology, Bldg. 93, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050 Australia. Phone: 61-2-9565-6155; Fax: 61-2-9565-6105; E-mail: a.basten{at}centenary.usyd.edu.au or j.sedgwick{at}centenary.usyd.edu.au
Received for publication 13 May 1998 and in revised form 14 August 1998.
M.C. Cook's present address is Department of Immunology, University of Birmingham, Medical School, Edgbaston, Birmingham, B15 2TT, UK. H. Körner's present address is Institute for Microbiology, Hygiene and Immunology, Wasserturmstrasse 3, D-91054 Erlangen, Germany.The authors thank D. Godfrey, P. Lalor, B. Scallon, G. Klaus, M. Kehry, B. Castle, H. Briscoe, D. Tarlinton, and B. Fazekas de St. Groth for generously sharing reagents. We appreciate the assistance of Karen Knight, James Croser, J. Webster, D. Strickland, and Danielle Avery.
This work was funded by a grant from the National Multiple Sclerosis Society of Australia (to H. Körner and J.D. Sedgwick), a National Health and Medical Research Council Program Grant (to A. Basten and J.D. Sedgwick), a University of Sydney Medical Foundation Program Grant (to P.D. Hodgkin) and postgraduate Scholarship (to M.C. Cook), a National Health and Medical Research Council postgraduate Scholarship (to D.S. Riminton), and a Wellcome Trust Senior Research Fellowship in Australia (to J.D. Sedgwick, held 1992-1996).
Abbreviations used in this paper BLR1, Burkitt lymphoma receptor 1; CFSE, 5-(and -6-)-carboxyfluorescein diacetate succinimidyl ester; FDC, follicular dendritic cell; GC, germinal center; HEL, hen egg lysozyme; LT, lymphotoxin; PALS, periarteriolar lymphoid sheath; PNA, peanut agglutinin; Tg, transgenic; TNFR-Ig, TNFR-1-IgG fusion protein; WT, wild-type.
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