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,§
*
Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia;
Intramural Research Support Program, Science Applications International Corp.-Frederick and Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD, 21702;
Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany;
§
Institute for Genetics, University of Cologne, Cologne, Germany; and
¶
Department of Clinical Pathology, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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(lt)-
and all lymphotoxin ß receptor (ltßr)-deficient mice
are completely devoid of lymph nodes (LNs); however, most lymphotoxin
ß (ltß)-deficient mice develop mesenteric LNs.
Tnf- and tnfrp55-deficient mice develop a
complete set of LNs, while ltß/tnfrp55
double-deficient mice lack all LNs, demonstrating cooperation between
LTß and TNFRp55 in LN development. Now we report that
ltß/tnf double-deficient mice develop the same set of
mucosal LNs as do ltß-deficient mice, suggesting that
ligands other than TNF signal through TNFRp55 during LN development.
These LNs retain distinct T and B cells areas; however, they lack
follicular dendritic cell networks. Structures resembling germinal
centers can be found in the LNs from immunized
ltß-deficient mice but not in ltß/tnf
double-deficient mice. Additionally, stromal components of the spleen
and LNs appear to be more severely disturbed in
ltß/tnf double-deficient mice as compared with
ltß-deficient mice. We conclude that LTß and TNF
cooperate in the establishment of the correct microarchitecture of
lymphoid organs. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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3 can bind to
two TNF receptors p55 and p75, while heterotrimeric
LT1/LTß2 is the main
ligand for the LTßR (4). Specific contributions of
LT/LTßR and TNF/TNFR signaling pathways to the development and the
maintenance of microarchitecture of peripheral lymphoid organs are
starting to emerge. Mice deficient in LT (5, 6) lack
proper T and B cell compartmentalization, marginal zone and FDC
networks, and do not develop germinal centers (GC) in the spleen upon
immunization. LTß-deficient mice have similar defects in spleen;
however, T and B cell zones are not as mixed as in LT-deficient mice
(7, 8). TNF-deficient mice have even milder
disturbances—marginal zone, albeit altered, is present in the spleen
of these mice—but FDC networks are absent and GCs are not formed
(9, 10, 11). Additionally, recent data by Alexopoulou et al.
(12) suggested that TNF expression may be disturbed in the
widely used neo-containing LT-deficient mice and thus
could have contributed to the severity of splenic white pulp
disorganization.
TNF-deficient mice develop lymph nodes (LNs) normally, whereas
LT-deficient mice lack all LNs, except for abnormal lymphoid
structures found in the mesenteric fat in 2–30% of mice (6, 13). LTß-deficient mice show an intermediate phenotype in this
regard, they usually develop mesenteric LNs (MLNs), and, more rarely,
sacral LNs (SLNs) and cervical LN. In these LNs, T and B cells
segregate well and peanut agglutinin (PNA)-binding clusters are formed,
but associated mature folicular dendritic cell (FDC) networks do not
develop (7, 8, 14).
Defects in the spleen of LTß-deficient mice (7, 8) are more severe than in TNF-/- mice (9). In contrast, several reports using biochemical rather than genetic inactivation of TNF (15, 16) suggested that TNF may play a distinct role in lymphoid organogenesis. Therefore, it was of considerable interest to determine whether a combined neo-free genetic excision of ltß and tnf genes may result in a more severe lymphoid deficiency as compared with single knockouts of the same genes.
In the present study, we generated and characterized a new mouse line
with a combined TNF/LT deficiency,
(LTß/TNF)
/ double-deficient mice. We
further dissected the contributions to the development and organization
of peripheral lymphoid tissues of the two main signaling pathways
involving LT and TNF. We show that under conditions where signaling
both by LT1ß2 via the
LTßR and by TNF via the TNFRp55 are abrogated, two previously
unrecognized effects become apparent: 1) redundant contributions of
alternative ligands (i.e., LT3 and/or LIGHT)
to the organogenesis of LNs, and 2) cooperative contributions of LTßR
and TNFRp55 signaling to the microarchitecture of lymphoid organs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Construction of the targeting vector, embryonic stem (ES) cell
transfection, and screening of homologous recombinants have been
previously described (7). Of the 43 ES cell clones with a
targeted insertion of the neo cassette, 15 clones revealed a
cointegration of the second and the third loxP sites without
cointegration of the fourth loxP motif of pTV2-TK. Two of these ES cell
clones were used for injection into C57BL/6 blastocysts
(17). Chimeric male mice were crossed to C57BL/6 mice to
obtain germline transmission of the
(LTß/TNF)+/T mutation.
(LTß/TNF)+/T mice were crossed to
Cre-transgenic "deleter" mice with ubiquitous expression of Cre
recombinase (18). As a result, the neo-cassette
and a region of the TNF/LT locus containing exon 3 of the
ltß gene and exons 3 and 4 of the tnf gene were
deleted in the mutant allele. The progeny was genotyped by PCR using
primers gtype1, 5'-CGG GTC TCC GAC CTA GAG ATC and gtype5a, 5'-CAG ACC
CTC ACA CTC AGT AAG. Correct excision of the portion of the TNF/LT
locus was further confirmed by Southern analysis using BamHI
digestion of genomic DNA and the SphI-PstI
portion of the LTß promoter as a probe. The Cre-transgene was crossed
out during further backcrossing to C57BL/6 mice. Heterozygous mice were
bred to obtain (LTß/TNF)/
double-deficient mice, which were then embryo rederived and maintained
under specific pathogen-free conditions.
Animals
All mice were generated on a mixed C57/BL6/129cv background and
then backcrossed to C57/BL6. LT-/- mice
(5) were purchased from The Jackson Laboratory (Bar
Harbor, ME). LTß-deficient mice (LTß/
mice) have been described previously (7). All mice were
maintained under specific pathogen-free conditions and used for
experiments between 8 and 12 wk of age. Animal care was provided in
accordance with the procedures outlined in the "Guide for the Care
and Use of Laboratory Animals" (National Institutes of Health
Publication No. 86-23, 1985).
RNA analysis
Total cellular RNA was extracted with Trizol reagent and used as
described by the manufacturer in RNAase protection assays with the
mCK-3 set of probes, including lt, ltß, and
tnf genes (PharMingen, San Diego, CA).
Immunizations
Where indicated, mice received a single i.p. injection of 50
µg of alum-precipitated nitrophenol-haptenated chicken 
-globulin
or 108 SRBC in PBS and were analyzed 8 days after
immunization.
Immunohistochemistry
Immunohistochemical analysis was performed as described
(2, 7). Hamster Abs to CD3 and rat Abs to B220, IgD,
IgM, CR1, and mucosal addressin cell adhesion molecule-1 were obtained
from PharMingen. Biotinylated PNA and the alkaline phosphatase staining
kit were purchased from Vector Laboratories (Burlingame, CA). ER-TR7
mAb was purchased from Biogenesis (Poole, U.K.). MOMA-1 mAb was
purchased from Research Diagnostics (Flanders, NJ). FDC-M1 Abs were
generously provided by Dr. M. Kosco-Vilbois (Serono Pharmaceutical
Research Institute, Geneva, Switzerland). Peroxidase-conjugated mouse
anti-rat IgG Abs (F(ab')2) were obtained from
Jackson ImmunoResearch (West Grove, PA). Alkaline
phosphatase-conjugated streptavidin and other reagents were obtained
from Sigma (St. Louis).
Flow cytometry
Flow cytometric analysis was performed on single-cell
suspensions as described (2). Biotin-, FITC-, or
PE-conjugated rat Abs to the following mouse surface markers were used:
Thy1.2 (clone 30H12), CD4 (clone RM4-5), and CD8 (clone 53-6.7) to
detect T cells; B220 (clone RA3-6B2) for B cells; and Gr1 (clone
RB6-8C5) and Mac1 (clone M1/70) for granulocytes and macrophages.
All primary Abs were obtained from PharMingen.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To address the possible redundancy of TNF/LT ligands in the
development of peripheral lymphoid organs we have generated a mouse
strain deficient in both LTß and TNF. Because the tnf and
lt genes are closely linked (19, 20, 21) it would
be virtually impossible to generate such mice by crossing single TNF
and LTß knockout mice. Therefore,
(LTß/TNF)/ mice were generated using
Cre-loxP technology, similarly to the previously described
LTß/ mice (7). In
particular, we generated ES cells with a partial homologous
recombination of the targeting vector pTV2-TK (7) and used
them for injection into C57BL/6 blastocysts. After germline
transmission, Cre-mediated recombination in vivo using "deleter"
mice (18) was employed to remove the selectable marker
(neo gene) and to create a 5.3-kb deletion (Fig. 1
A). This deletion (confirmed
by Southern analysis; Fig. 1B) included the third exon of
the ltß gene (encoding most of the extracellular portion
of this cytokine) and the third and the fourth exons of the
tnf gene (encoding the entire secreted portion of the TNF
protein) and did not allow the expression of functional LTß and TNF
mRNAs.
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/ mice (data not shown),
similarly to the infiltrates described for
LTß/ mice (7),
LT-/- mice (6), and
LTßR-/- mice (2). Transcription
of the lt gene was not disturbed by the deletion, as
confirmed by RNase protection assay performed with total RNA isolated
from Con A-activated splenocytes (Fig. 1
C). TNF and LTß do not cooperate in LN organogenesis
Peripheral lymphoid organs of
(LTß/TNF)/ mice were examined. No visible
Peyer’s patches were found and no inguinal, brachial, axillary, iliac,
or popliteal LN could be detected by histopathological examination
(data not shown). However, MLNs and sometimes SLNs could be readily
detected (in 15 of 17 and 6 of 17 mice, respectively). Thus, lymphoid
organs in (LTß/TNF)/ mice develop
similarly to the previously described
LTß/ mice (MLNs, 15 of 23; SLNs, 6 of
23). The anatomical shape of MLNs was unusual in both single
ltß- and double ltß/tnf-deficient animals. In
most cases, only one large, spherical MLN was found in mutant mice at a
point where the root of the mesentery merges with the parietal
peritoneal mesothelium, as opposed to a chain of three elongated LN
segments normally present along the mesenteric artery in wild-type
mice. The specific anatomical location of the MLN found in
LTß/ and
(LTß/TNF)/ mice suggests that some of the
segments of the MLN draining the lymph from the gut (small bowel,
cecum, and sigmoid colon) may be missing in these animals.
MLNs from (LTß/TNF)/ mice were examined
by immunohistology and compared with MLNs from wild-type mice and from
LTß/ mice (Fig. 2). As expected, FDC networks were absent
in all mutant mice as assessed by staining for CR1 (Fig. 2) or FDC-M1
(data not shown).
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/ mice as compared with
LTß/ mice. Both types of mice retained a
distinct segregation of lymphocytes into a superficial cortical B cell
zone and a deep cortical T cell zone. Furthermore,
LTß/ mice were able to form structures in
the superficial cortex that resembled GCs in MLN upon immunization
(Fig. 2), in agreement with the recent report by Koni and Flavell
(14). Because CR1+ FDC networks
appeared to be absent in LTß/ mice, it is
not possible to state with certainty if these GC-like structures were
segregated into light zone or dark zone compartments. However, small
IgD+/IgM+ lymphocyte
coronas and IgM+/PNA+ GCs
were found both in unstimulated and in Ag-stimulated mice (data not
shown).
In contrast to LTß/ mice,
PNA+ B cells found in the LNs from
(LTß/TNF)/ mice were scattered and did
not form foci resembling GCs. There was segregation of
B220+ B cells to the superficial cortex and of
CD3+ T cells to the deep cortex of MLN, but in
areas where one would expect to find B cell follicles, only scattered
individual PNA+ B cells were found (Fig. 2).
Examination of the underlying fibroblastic reticular cell (FRC)
architecture with ER-TR7 Ab (22) provided useful
correlates. In wild-type mice, there was a delicate FRC network in the
deep cortex (paracortex) that formed the narrow perivenular channel,
FRC corridors, and cortical columns that are characteristic of this
compartment (23). In the superficial cortex, this delicate
pattern undergoes an abrupt transition where there are interfaces with
B cell follicles (Fig. 2, bottom row). The corona usually
retains the delicate pattern of the paracortex but GCs are separated
from the corona by an FRC "barrier" and the GC areas contain broad
zones that are relatively free of fibroblastic reticulum. This may
presumably be to accommodate the FDC network. Regardless of the reason,
the FRC pattern usually reflects the presence of structures like
GCs.
In the LTß/ mice, the reticulum of the
deep cortex was coarser than in the wild-type mice, with thicker fibers
and wider spaced corridors. In these mice, the transition of FRC at
GC-like structures was less distinct than that seen in the wild-type
mice, but some alteration in the reticulum pattern in the areas of
PNA+ B cell foci was evident, with a ring of more
dense stromal components surrounding PNA+ area
(Fig. 2, bottom row). In contrast, in
(LTß/TNF)/ mice the coarse pattern of the
fibroblastic reticulum was uniform across the T-dependent and
B-dependent cortex and no GC-like architectural transitions were seen.
Apparently, the loosely scattered PNA+ B cells
were of insufficient aggregate size to have an impact on the underlying
reticulum, so the cortical pattern extended to the subcapsular
sinus.
We concluded that PNA+ B cell clusters resembling
GCs can be formed in the absence of FDC network (as assessed by CR1 and
FDC-M1 staining) in LTß/ but not in
(LTß/TNF)/ mice, suggesting independent
contribution of TNF into underlying signaling mechanism. We also
concluded that stromal components of the MLN were more severely
disturbed in the double knockout.
In an attempt to characterize cervical LNs in
(LTß/TNF)/ mice, we performed
immunohistological examination of LN-like structures found in the
normal location of cervical LNs (data not shown). However, we were
unable to identify any true cervical LNs either in
(LTß/TNF)/ mice (n = 5)
or in LTß/ mice (n = 7).
This result, which is somewhat contradictory to the published
observations (7, 8), may be due to the fact that the mice
used in this study have been rederived by embryo transfer and
maintained under specific pathogen-free conditions thereafter or due to
a low incidence of cervical LNs in this mouse model.
The double ltb and tnfrp55 knockout mice
(24) lack all LNs, including MLN and SLN (see Table I). Because inactivation of the TNFRp55
gene disrupts signaling by both TNF and LT3,
the comparison with the (LTß/TNF)/ model
suggests that it is binding of LT3, and not of
TNF, to TNFRp55 that is important for cooperation with LTßR signaling
for the development of the mucosal subset of LNs.
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However, the absence of LNs from wild-type mice simultaneously injected
in utero with LTßR-Ig and anti-TNF mAb (1) is in
apparent contradiction with our results. Several explanations can be
offered. First, if effects of TNF are mediated by cell-surface-bound
ligands, then TNF-bearing cells may be lysed in the Ab-injection
experiment by a complement-mediated mechanism. Second, LN genesis may
involve an additional signaling through LTßR by LIGHT
(25) or by another as yet unidentified ligand, and such
signaling would be disrupted in the model of Rennert et al. but not in
(LTß/TNF)/ mice. This hypothesis is
further supported by the report on the mice with genetic inactivation
of LTßR (2), which do not develop any LNs.
Collectively, our data support the cooperation of TNFRp55 and LTßR
signaling cascades in organogenesis of LNs and suggest a distinct role
for LT3-TNFRp55 signaling. Together with
observations by Koni and Flavell (24), this represents a
novel biological function of LT3 detected in
vivo in a nontransgenic model. Previously evidence for distinct
function of LT3-TNFRp55 interaction in
lymphoid organogenesis and inflammation was provided by a series of
elegant studies using LT transgene under the control of the rat
insulin promoter (26, 27, 28, 29). The hypothesis concerning the
role of an additional LT-specific receptor in LN development
(30) is not supported by the phenotype of
tnfrp55-/-ltß-/-
(24) or (LTß/TNF)/ mice
(this report).
The development of LNs is a complex process involving several cell
lineages and multiple signaling pathways. Nevertheless, the role of
LT-LTßR has been reinforced by the findings on aly/aly
mice (31) in which case the defect is caused by mutation
in carboxyl-terminal end of NF-
B-inducing kinase (NIK)
(32). This result also places NIK (33) in the
signaling cascade downstream of LTßR (and probably of some other
receptors of the TNFR superfamily) and not of TNFRp55
(32). Additionally, opgl-/-
mice (34) also completely lack LNs. Osteoprotegerin (OPG)
ligand (OPGL) (also known as TNF-related activation-induced cytokine
(TRANCE), receptor activator of NF-B ligand (RANKL), or osteoclast
differentiation factor (ODF); Refs. 35, 36, 37) is a ligand
for OPG and RANK that is also a member of the TNFR superfamily. It is
possible that the OPGL/(OPG/RANK) signaling pathway shares some
downstream molecules with LTßR signaling pathways (see Ref.
35). Whether NIK is involved in this signaling remains to
be demonstrated. Alternatively, OPG/RANK signaling may be required at a
different step in LN development.
TNF and LTß cooperate in the maintenance of splenic microarchitecture
Spleens of (LTß/TNF)/ mice were
studied by immunohistochemistry after i.p. immunization with T
cell-dependent Ags SRBC (Fig. 3) or
nitrophenol-haptenated chicken -globulin (data not shown). Wild-type
littermate controls, LTß/
(7), and LT-/- (5)
mice were examined in parallel (Table I). As a common feature, FDC
networks could not be detected in any of the mutant mice using staining
for CR1 (Fig. 3) or FDC-M1 (data not shown), and there were no
clustered PNA-positive cells in B cell areas, although some aberrant
PNA staining with a variable pattern could be detected around central
arterioles and blood vessels (Fig. 3). In agreement with the published
data, the staining of the marginal zone of the spleen by mucosal
addressin cell adhesion molecule-1 and MOMA-1 markers was absent in
(LTß/TNF)/,
LTß/, and
LT-/- mice (data not shown).
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and Table I). Spleens of LTß/
mice still retained relatively distinct B cell zones, while in the
double-deficient mice B cell areas were smaller and much less defined
(Fig. 3), even though the numbers of B and T cells in the spleen of the
double (LTß/TNF)/ mice were not changed
as assessed by flow cytometry analysis (data not shown) The relative
numbers of T and B cells in spleen of
(LTß/TNF)/ mice (15–20% and 30–35%,
respectively) as well as the absolute numbers of lymphocytes in spleen
(0.8–1.5 x 108) and in thymus
(1.3–1.7 x 108) were not significantly
different from the wild-type mice, while the white cell counts in blood
and peritoneum were two to three times higher in
(LTß/TNF)/ mice as compared with the
wild-type mice, the phenomenon previously described for
LT-/- (5, 6) and
LTß/ mice (7, 8).
The profound defect of the splenic T/B cell segregation was further
characterized using labels specific for the stromal components of the
spleen. Labeling with ER-TR7 Ab, which detects reticular fibroblasts
and blood vessel walls (22), revealed that stromal
components of the spleen that support spatial organization of the
lymphoid tissues (38) were more disturbed in
(LTß/TNF)/ mice than in
LTß/ mice (Fig. 3). ER-TR7-positive
stromal elements in the spleen of LTß/
mice, even though markedly disorganized in comparison with the wild
type, still formed a distinct ellipsoid-like structure confining the
white pulp area. In contrast, ER-TR7 labeling of the spleen of
(LTß/TNF)/ mice did not reveal a clear
boundary between the red and white pulp (Fig. 3). Routine chemical
stains for elastic or collagen fibers (Orcein and Masson’s TriChrome)
(39) revealed an increased density of these connective
tissue elements around the central arterioles in the spleen of
(LTß/TNF)/ mice as compared with
LTß/ and wild-type mice (Fig. 4). This accumulation of the connective
tissue around central arterioles was not due to insufficient number of
T cells (see above) and may be responsible for the deficient
compartmentalization by affecting lymphocyte migration or by providing
dislocated chemotactic or adhesion signals (40).
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- or LTß-deficient mice. A
substantial decrease with regard to expression levels of the B
lymphocyte chemoattractant and of the secondary lymphoid tissue
chemokine reported in association with LT deficiency
(42) is also observed in both
(LTß)/ and
(LTß/TNF)/ mice (without substantial
difference between these two models, data not shown). In the future, it
will be interesting to determine whether any of these chemokine genes
may be under direct control of LTßR or TNFR55 signaling.
In summary, our genetic data demonstrate that there is an independent
contribution of TNF to the LT-dependent maintenance of the
microarchitecture of the spleen and LN. Our data also suggest a
distinct role of LT3-TNFRp55 interaction in
the development of mucosal LNs.
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Acknowledgments |
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Footnotes |
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2 D.V.K., M.B.A., and A.V.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Dmitry V. Kuprash, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, 117984 Moscow, Russia. E-mail address:
4 Abbreviations used in this paper: LT, lymphotoxin; GC, germinal center; FDC, follicular dendritic cell; FRC, fibroblastic reticular cell; LN, lymph node; MLN, mesenteric LN; SLN, sacral LN; OPG, osteoprotegerin; PNA, peanut agglutinin; ES cell, embryonic stem cell; NIK, NF-B-inducing kinase.
Received for publication July 23, 1999. Accepted for publication September 30, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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ß and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189:403.This article has been cited by other articles:
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D. V. Kuprash, M. B. Alimzhanov, A. V. Tumanov, S. I. Grivennikov, A. N. Shakhov, L. N. Drutskaya, M. W. Marino, R. L. Turetskaya, A. O. Anderson, K. Rajewsky, et al. Redundancy in Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) Signaling In Vivo: Mice with Inactivation of the Entire TNF/LT Locus versus Single-Knockout Mice Mol. Cell. Biol., December 15, 2002; 22(24): 8626 - 8634. [Abstract] [Full Text] [PDF]
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 S. Scheu, J. Alferink, T. Potzel, W. Barchet, U. Kalinke, and K. Pfeffer Targeted Disruption of LIGHT Causes Defects in Costimulatory T Cell Activation and Reveals Cooperation with Lymphotoxin {beta} in Mesenteric Lymph Node Genesis J. Exp. Med., June 17, 2002; 195(12): 1613 - 1624. [Abstract] [Full Text] [PDF]
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V. N. Ngo, R. J. Cornall, and J. G. Cyster Splenic T Zone Development Is B Cell Dependent J. Exp. Med., December 3, 2001; 194(11): 1649 - 1660. [Abstract] [Full Text] [PDF]
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T. Plitz and K. Pfeffer Intact Lysosome Transport and Phagosome Function Despite Kinectin Deficiency Mol. Cell. Biol., September 1, 2001; 21(17): 6044 - 6055. [Abstract] [Full Text] [PDF]
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P. D. Rennert, P. S. Hochman, R. A. Flavell, D. D. Chaplin, S. Jayaraman, J. L. Browning, and Y.-X. Fu Essential Role of Lymph Nodes in Contact Hypersensitivity Revealed in Lymphotoxin-{alpha}-deficient Mice J. Exp. Med., May 29, 2001; 193(11): 1227 - 1238. [Abstract] [Full Text] [PDF]
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Y. Wang, J. Wang, Y. Sun, Q. Wu, and Y.-X. Fu Complementary Effects of TNF and Lymphotoxin on the Formation of Germinal Center and Follicular Dendritic Cells J. Immunol., January 1, 2001; 166(1): 330 - 337. [Abstract] [Full Text] [PDF]
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