By
From the * Section of Immunobiology and the Howard Hughes Medical Institute, Yale University
School of Medicine, New Haven, Connecticut 06520
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Abstract |
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Lymphotoxin (LT
) signals via tumor necrosis factor receptors (TNFRs) as a homotrimer
and via lymphotoxin
receptor (LT
R) as a heterotrimeric LT
1
2 complex. LT
-deficient
mice lack all lymph nodes (LNs) and Peyer's patches (PPs), and yet LT
-deficient mice and
TNFR-deficient mice have cervical and mesenteric LN. We now show that mice made deficient in both LT
and TNFR type 1 (TNFR1) lack all LNs, revealing redundancy or synergism between TNFR1 and LT
, acting presumably via LT
R. A complete lack of only PPs in
mice heterozygous for both lt
and lt
, but not lt
or lt
alone, suggests a similar two-ligand
phenomenon in PP development and may explain the incomplete lack of PPs seen in tnfr1
/
mice.
![]() |
Introduction |
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Studies on mice genetically deficient in various secondary lymphoid organs are increasing our understanding
of the requirement or otherwise for these highly organized
structures in immune function, from antiviral immunity (1)
to autoimmunity (2). Hox11/
mice lack a spleen (3),
whereas aly/aly mutant mice lack LNs and have a disorganized spleen (4, 5). Also, mice made deficient in the putative chemokine receptor BLR1 lack inguinal lymph nodes and fail to form primary B cell follicles in the spleen (6). Our studies have involved members of the TNF receptor
and ligand families (7, 8). Studies of TNF family members
are not only providing insight into the intricate microarchitecture of immune cell responses in lymphoid organs but
also of chronic inflammatory states (9), such as the phenomenon termed lymphoid neogenesis (10).
TNF- and TNF-
(lymphotoxin
; LT
)1 are the archetypal ligands of a growing family, which includes CD30
ligand (L), CD40L, FasL, TRAIL, and lymphotoxin
(LT
) (11, 12). LT
was discovered by virtue of its ability
to anchor LT
to the cell surface, without which LT
is
secreted as a homotrimer (LT
3) (13, 14). LT
/
complex
itself is a trimer with a predominant form (LT
1
2) that binds LT
R, and a minor form (LT
2
1) that binds TNF
receptor type 1 (TNFR1) (15). Both forms of LT
are
produced by activated lymphocytes and NK cells (12, 18).
Historically, LT3 is known as a factor that causes cytotoxicity and inflammation, and signals via TNFR1 and
TNFR2 (9, 19, 20). Although LT
/
complexes do not
appear to mediate inflammation (21), pleiotropic effects of
LT
R cross-linking are now emerging, including cytotoxicity (17, 22), chemokine induction (23), and integrin upregulation (21). Studies with lt
/
mice and lt
/
mice
are beginning to address the in vivo significance of these facets of LT
and LT
biology (2). However, initial studies of lt
/
mice were dominated by the unexpected observation of a complete lack of LNs and Peyer's patches (PPs), as
well as a disorganized spleen lacking follicular dendritic
cells and germinal centers (24). Since mice deficient in
TNFR have LNs, it had been assumed that the LT
/
complexes were responsible rather than LT
3. However, we recently showed that this explanation was not entirely
correct (28). Specifically, we determined that lt
/
mice
retain mesenteric LNs (MLNs) and to a certain extent, cervical LNs, both of which drain mucosal surfaces. It was
therefore a paradox that these LNs are absent in mice that
lack the LT
3 ligand and yet they are present in mice that
lack the known receptors TNFR1 and TNFR2.
We now report that mice made deficient in both
TNFR1 and LT lack MLNs. We have thus revealed a redundancy or synergism between TNFR1 and LT
(presumably signaling via LT
R) that warrants further investigation in other aspects of TNFR1 and LT
biology. Lt
/
mice and lt
/
mice were derived as littermates by interbreeding, and unambiguously confirmed the lack of MLNs
in lt
/
mice and their presence in lt
/
mice. Surprisingly, the latter studies also revealed a complete and specific
lack of only PPs in lt
+/
lt
+/
mice. This presents a
unique mouse model for the study of gastrointestinal immunology and suggests that two LT
ligands are involved
in PP as well as MLN development, and may explain the
incomplete lack of PPs seen in tnfr1
/
mice.
![]() |
Materials and Methods |
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Mice.
ltBone Marrow Chimeras.
Hosts were exposed to 950 rads at 6-8 wk of age and, 1 d later, were given 2 × 106 total nucleated bone marrow cells intravenously in 0.2 ml of PBS. Bone marrow was from sex-matched 8-12-wk-old C57BL/6 Ly5.1 mice. 8 wk after irradiation, the relative ratio of CD45.1+ donor cells versus CD45.2+ host cells in peripheral blood was determined by fluorocytometry. Both biotin-conjugated anti-CD45.1 and FITC-conjugated anti-CD45.2 were from PharMingen (San Diego, CA). The degree of chimerism was >95% in all cases. 9-10 wk after irradiation, recipients were challenged intraperitoneally with 0.1 mg of chickenPathology.
Visualization of bracheal, axillary, inguinal, and popliteal LNs (30) was aided in some experiments by injecting 50 µl of india ink into each footpad of the mice 3-4 h before culling. The prominence of PPs was greatly increased by immersing the intestine in 10% (vol/vol) acetic acid for 5 min before preservation in 10% neutral-buffered formalin. Hematoxylin and eosin staining was done on paraffin sections using standard procedures.Immunohistology.
Mice were challenged intraperitoneally at 6-8 wk of age with 0.1 mg of chicken ![]() |
Results |
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Initial reports of the phenotype of two independently generated
lt/
mouse strains differed in that one indicated that
MLNs were absent (24), whereas the other indicated that
lymphoid structures were present in the mesentery of 4 out
of 14 mice (25). Most recently, among ~500 lt
/
mice
examined for MLNs, only 10 had a single MLN (33). It
was thus suggested that the frequency of occurrence of
MLNs in lt
/
mice may vary depending on how the
mice are housed (33). If true, this would perhaps apply
equally to lt
/
mice, which we described as consistently
having MLNs (28). Furthermore, Alimzhanov et al. independently generated lt
/
mice and found that only
~75% of these mice have MLNs (34). It was therefore also
conceivable that there are effects of background genes, although all mice examined were on a mixed background of 129/Sv and C57BL/6. The studies here were begun to examine these issues and determine why lt
/
mice have
MLNs despite the fact that lt
/
mice mostly do not.
The lt and lt
genes are separated by only ~6 kbp in
the MHC locus (12). Thus, we reasoned that it would be
possible to generate lt
/
mice and lt
/
mice as littermates by interbreeding mice which are heterozygous for
both lt
and lt
(lt
+/
lt
+/
mice). In this way, 137 progeny were generated and genotyped as described in Materials and Methods. Lt
/
, lt
/
, and lt
+/
lt
+/
mice occurred in a relatively normal Mendelian fashion (n = 31, 40, and 66, respectively). Some of these mice were examined at 6-8 wk of age. Lt
/
mice did not have MLNs (n = 14), whereas almost all of their lt
/
littermates did (n = 25). A single lt
/
mouse out of 25 appeared to lack
MLNs.
Unlike lt/
and lt
/
mice, the above heterozygous
lt
+/
lt
+/
mice had all LNs (n = 30), except that two
mice had only one inguinal LN and one mouse had none.
Surprisingly, however, lt
+/
lt
+/
mice showed a complete lack of PPs (n = 30), whereas both lt
+/
mice (n = 13) and lt
+/
mice (n = 14) have PPs as well as all LNs.
Having made this observation, we examined lt
+/
lt
+/
mice further. At 6-8 wk of age, the gross spleen architecture was normal by hematoxylin and eosin histology (data
not shown). Immunohistology for complement receptor 1 in the spleen (done as previously described; reference 28)
revealed the presence of follicular dendritic cells (data not
shown). Also, splenic germinal centers were formed in discrete
B cell follicles after intraperitoneal challenge, except there
appeared to be some disorganization among IgM+IgDlo/
marginal zone B cells (Fig. 1 E). Lt
/
mice (24) and
lt
/
mice (28, 34) have severe defects in all of these aspects of lymphoid organogenesis.
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The organization of the MLNs of lt+/
lt
+/
mice was
also relatively normal (Fig. 1 F). As previously noted (28),
the organization of the MLNs of lt
/
mice is not normal
in that there appears to be a generalized B cell infiltration,
but B cell follicles are found around the rim of MLNs and
germinal center B cell clusters are formed despite the absence of follicular dendritic cells (reference 28; Fig. 1 D).
The lack of PPs in lt+/
lt
+/
mice was confirmed in
progeny from intercrossing lt
/
mice with lt
/
mice (n = 4). Bone marrow chimeras were also generated using wild-type bone marrow, to examine whether or not the lack of
PPs was reversible. None of the lt
+/
lt
+/
recipients
showed any sign of PPs 10-12 wk after irradiation, but
they did have LNs (n = 9). None of the lt
/
recipients
had MLNs (n = 8), but all of the lt
/
recipients did (n = 11). None of the lt
/
recipients or lt
/
recipients had
PPs. Lt
+/+ wild-type recipients had MLNs and PPs (n = 4).
Both lt/
mice and dtnfr
/
mice have MLNs, and yet lt
/
mice do
not. This led us to propose that LT
may act without LT
(i.e., as LT
3) via an as yet unidentified receptor (28). To
test this hypothesis, we generated mice lacking both LT
and TNFR and examined them for the presence of MLNs.
Since TNFR-deficient mice were originally obtained as
dtnfr
/
mice, the first mice generated here were lt
/
dtnfr
/
mice. At 6-8 wk of age, lt
/
dtnfr
/
mice
showed a complete lack of MLNs (n = 10), whereas lt
+/
dtnfr
/
mice still had MLNs (n = 5).
In a similar way to lt/
mice, it is conceivable that the
apparent absence of MLNs in lt
/
dtnfr
/
mice is due to
a possible lack of immune competence and/or lymphocyte homing, and that this might be reversed after reconstitution
with wild-type bone marrow. We therefore generated
wild-type bone marrow chimeras. However, none of the
bone marrow chimeras had MLNs 10-12 wk after reconstitution (n = 11).
In the meantime, we also generated lt/
tnfr1
/
and
lt
/
tnfr2
/
mice. The latter had MLNs (n = 4) but lt
/
tnfr1
/
mice clearly did not (n = 5). Most lt
/
tnfr1+/
littermates (n = 5) had one small MLN (Fig. 2). One lt
/
tnfr1+/
littermate did not appear to have MLNs, whereas
another had two small MLNs. This may be explained by
the fact that tnfr1 heterozygosity is known to result in a
partial phenotype at least in some respects (35), but at the
same time lt
+/
tnfr1+/
mice had MLNs of a normal size
(n = 13).
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![]() |
Discussion |
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The study reported here extends our knowledge of the
roles of TNF ligand/receptor family members in lymphoid
organogenesis (Table 1). Based on several observations, we
had previously hypothesized that both TNFR1 and LTR
may be involved in PP development (28). First, both lt
/
mice (24, 25) and lt
/
mice (28, 34) completely lack PPs.
Second, Rennert et al. observed a complete lack of PPs in
mice administered recombinant soluble LT
R in utero
(36). Third, tnfr1
/
mice lack PPs but have reduced numbers of residual lymphoid aggregates (37). Defective PP development was also reported recently with an independently generated tnfr1
/
mouse strain (29). Others reported
that tnfr1
/
mice have PPs but that they appear flattened
due to a lack of B cell follicle structures (38). However,
even this study noted that tnfr1
/
mice have on average
only two to four such PPs compared with six to eight PPs
in the wild-type control mice (38).
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In this study, we show the existence of a gene dosage effect that is consistent with a role for both TNFR1 and
LTR in PP development. That is, lt
+/
lt
+/
mice specifically lack only PPs, but lt
+/
mice and lt
+/
mice do
not. If LT
and LT
form a single species that signals via a
single receptor, it might be expected that either LT
or LT
would be the limiting factor and that heterozygosity
in either lt
or lt
alone should result in the lack of PPs
seen in lt
+/
lt
+/
mice. However, this is not the case.
Only when both lt
and lt
are heterozygous does insufficiency become evident. One interpretation would be that
two ligands (e.g., LT
3 and LT
1
2 signaling via TNFR1
and LT
R, respectively) are involved in PP development, and that heterozygosity in either one or the other alone is
not enough to cause a complete loss of PP development.
This two-receptor model might therefore provide an explanation for the partial defect in PP development seen in tnfr1
/
mice.
Clearly, our results show that both TNFR1 and LT are
involved in MLN development, even though both tnfr1
/
mice and lt
/
mice have MLNs. TNFR1 also functions
independently of TNFR2 in this regard, as lt
/
tnfr2
/
mice still have MLNs. We have thus revealed a previously
unappreciated relationship between TNFR1 and LT
(presumably acting via LT
R). An explanation for the lack
of MLN in lt
/
mice might therefore be that LT
deficiency actually eliminates both ligands of the relationship (i.e.,
LT
3 and LT
1
2 signaling via TNFR1 and LT
R, respectively). LT
3 itself is not believed to bind LT
R (16, 17).
However, having said this, it has been indicated that
ltr
/
mice lack MLNs (34). Thus, the relationship between TNFR1 and LT
R may be one of synergism with
LT
R as the dominant partner. At the same time, the presence of MLN in lt
/
mice would imply that LT
R has a
ligand besides the LT
/
complex. Indeed, Mauri et al.
have very recently described a new LT
R ligand (LIGHT)
as well as a new LT
3 receptor, the herpesvirus entry mediator, expressed by lymphocytes (39).
The molecular basis for the relationship between TNFR1
and LT (presumably via LT
R) remains to be determined. It is conceivable that TNFR1 and LT
R signaling
in MLN development is simultaneous and that they interact at the level of intracellular signal transducers. Certainly,
activation of LT
R has been shown to potentiate TNF-
cytotoxicity, possibly reflecting cross-talk between signaling pathways (17, 22). Ligation of LT
R causes recruitment of TNFR-associated factor family members (40),
and activation of NF-
B and cell death by distinct signaling
pathways (42, 43).
Thus far, our studies of lt/
mice have evaluated the
defects in lymphoid organogenesis (reference 28 and this
study). We are now beginning to examine whether or not
LT
has roles in vivo in other respects. Certainly, in vitro
studies have shown that signaling via LT
R causes cytotoxicity to some cell lines (17, 22), chemokine expression
(23), and integrin upregulation (21). It remains to be seen
whether or not the relationship between TNFR1 and LT
(presumably via LT
R) in gut-associated lymphoid tissue
development extends to any other facets of biology. With
this in mind, caution is advised when interpreting the in vivo role (or rather, apparent lack thereof ) of LT
and
TNFR1 based on studies of lt
/
mice and tnfr1
/
mice
alone.
Finally, lt+/
lt
+/
mice may prove to be a useful PP-less mouse model, not only for the study of gastrointestinal
infection, but also of oral tolerance, oral vaccination, and
chronic disorders such as inflammatory bowel disease (44-
46). Lt
+/
lt
+/
mice are being further characterized, particularly with respect to the subtle defect observed in
splenic marginal zone organization. Although it remains
possible that lt
+/
lt
+/
mice have other as yet unidentified defects, unlike any other previously described mouse,
these mice specifically and completely lack only PPs and do
not appear to have any of the major abnormalities associated with lt
/
and lt
/
mice.
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Footnotes |
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Address correspondence to R.A. Flavell, Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, FMB 412, New Haven, CT 06520. Phone: 203-737-2216; Fax: 203-785-7561; E-mail: richard.flavell{at}qm.yale.edu
Received for publication 11 February 1998 and in revised form 8 April 1998.
We thank Jacques Peschon (Immunex Corp., Seattle, WA) for tnfr/
mice; Frank Wilson, Cindy Hughes,
and Debbie Butkus for technical assistance; and Fran Manzo for secretarial assistance.
This work was supported by the Howard Hughes Medical Institute (R.A. Flavell) with the aid of grants from the Human Frontiers Science Program (to P.A. Koni) and the American Diabetes Association (to R.A. Flavell). Richard A. Flavell is an Investigator of the Howard Hughes Medical Institute.
Abbreviations used in this paper: dtnfr
/
, mice deficient in both TNFR1
and TNFR2;
LT, lymphotoxin;
MLN, mesenteric lymph nodes;
PPs, Peyer's patches.
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