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Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
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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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The development of both CD40- and CD154-deficient mice as well as the use of blocking Ab has provided the ability to test the role of CD40/CD154 interaction in a wide range of infectious disease systems (7). This approach has revealed that there is a marked heterogeneity in the requirement for CD40/CD154 for appropriate immune response development depending upon the pathogen investigated, with the majority of research in this area focusing on proinflammatory, Th1-inducing pathogens. However, the outcome of infection with pathogens that induce Th2 responses in such animal models or in individuals with hyperIgM syndrome is much less clearly defined.
The parasitic helminth Schistosoma mansoni is a major public health problem on several continents. The immune response to this intravascular parasite is strongly Th2 in nature (8), and it is clear that this response provides protection against potentially life-threatening aspects of ongoing infection as well as against superinfection (9, 10, 11, 12). However, the mechanisms that control the development of this response, how it is regulated, and how it serves its protective role are still largely unknown.
We have investigated the importance of CD40/CD154 interaction in the
development of an appropriate immune response to S. mansoni
by infecting mice that are genetically deficient in CD154. Previous
work suggested that the CD40/CD154 interaction may be important for Th2
development, because coinjection of S. mansoni eggs with
anti-CD40 Ab results in down-modulation of Th2 development
(13). Our data have revealed a crucial role for CD154 in
Th2 response development during active infection with S.
mansoni. We have found that CD154-/- mice
infected with S. mansoni mount a greatly impaired Th2
response and suffer from severe morbidity, exhibiting extreme lung
pathology and cachexia that eventually lead to death. This sequence of
events occurs in the absence of any overt inflammatory response,
suggesting that mediators such as NO and TNF-
are not responsible
for the morbidity observed in CD154-/-
animals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD154-/- mice were obtained from The
Jackson Laboratory (Bar Harbor, ME); they were bred in-house and
maintained in filter-topped isolator cages, with Bactrim (HiTech
Pharmaceutical, Amityville, NY)-supplemented water. Wild-type (WT)
C57BL/6 mice (Taconic Farms, Germantown, NY) were used as controls and
similarly maintained on Bactrim-supplemented water. Biomphalaria
glabrata snails infected with both sexes of S. mansoni
and Puerto Rican strain NMRI were obtained from Dr. F. Lewis
(Biomedical Research Institute, Rockville, MD). Mice were infected
percutaneously with 
70 cercariae, weighed regularly, and euthanized
after significant weight loss (>20%) was observed in
CD154-/- animals. Adult worms were recovered by
perfusion as previously described (14), and samples of
lung, liver, and small intestine were collected to quantitate egg
deposition (15). Additional samples of lung, liver, and
small intestine were fixed in neutral buffered formalin before staining
and histologic examination. Liver granuloma areas were measured on
Masson’s Trichrome-stained sections using Image-Pro Plus software
(Media Cybernetics, Silver Spring, MD). A minimum of 15 single egg
granulomas in clear transverse section were measured per sample. For
infection with Toxoplasma gondii, mice were injected i.p.
with 2 x 105 TS4 tachyzoites.
Reagents
Soluble egg Ag (SEA) was prepared from isolated schistosome eggs as previously described (16, 17). Soluble tachyzoite Ag (STAg) was prepared as described previously (18). SEA (50 µg/ml), STAg (20 µg/ml), and plate-bound anti-CD3 mAb (BD PharMingen, San Diego, CA; 0.5 µg/well) were used to stimulate in vitro cultures.
Cell culture and cytokine measurement
Mesenteric lymph node (MLN) or spleen cells were harvested, and
single-cell suspensions were prepared as previously described
(19). Cells were counted using trypan blue and resuspended
at 107/ml in DMEM (Sigma-Aldrich, St. Louis, MO)
containing 100 U/ml penicillin plus 100 µg/ml streptomycin (Life
Technologies, Gaithersburg, MD), 10 mM HEPES (Life Technologies), and 2
mM L-glutamine (Life Technologies). Cells
(106/well) were cultured in 96-well flat-bottom
plates in 5% CO2 at 37°C with or without the
SEA (50 µg/ml) or plate-bound anti-CD3 (0.5 µg/well).
Supernatants were harvested from 24- or 72-h culture and stored at
-20°C for subsequent cytokine analysis by ELISA. Cytokine ELISAs
were performed on culture supernatants or plasma samples using paired
mAb purchased from BD PharMingen or purified from hybridoma
supernatants in our laboratory, except for TNF-, where the TNF-
duoset (R&D Systems, Minneapolis, MN) was used. NO production was
measured by Greiss reaction (20). Standard ELISPOT
protocols were followed to quantitate the number of IL-4- and
IFN-
-producing MLN cells, using 0.1 M 2-amino-2 methyl-1-propanol
buffer containing 0.6% SeaPlaque agarose and
5-bromo-4-chloro-3-indolyl phosphate (1 mg/ml) as a substrate. For
peripheral blood counts, thin blood smears were applied to glass
slides, air-dried, and fixed in methanol before staining using Hema-3
(Fisher Scientific, Pittsburgh, PA). The proportion of eosinophils was
determined by morphologic examination of at least 300 cells/sample in
random fields.
Flow cytometry
Expression of surface MHC class II on Mac-1+ or B220+ cells was quantified by flow cytometry using FITC- or PE-conjugated Ab (I-Ab, B220 or Mac-1), purchased from BD PharMingen. Samples were analyzed using a FACSCaliber flow cytometer and CellQuest software (BD Biosciences, Franklin Lakes, NJ). Proliferation was measured by CFSE (Molecular Probes, Eugene, OR) labeling of freshly isolated spleen or MLN cells before culture for 5 days with or without 50 µg/ml SEA or plate-bound anti-CD3. Cells were then fixed and analyzed as described above.
Statistical analysis
The Student t test was used to determine the statistical significance between groups. A value of p < 0.05 was considered a significant difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In comparison to infected WT mice, infected
CD154-/- mice showed increasingly severe
morbidity from around 7 wk postinfection (Fig. 1
A). Morbidity was
characterized by loss of activity, deterioration of coat condition,
deterioration of posture, and weight loss. Left unchecked, this
eventually culminated in the death of infected
CD154-/- mice within 2 wk of the initiation
of weight loss (Fig. 1B). Development of these symptoms was
dependent upon patent infection and coincided with the onset of egg
laying, as CD154-/- mice infected with male
parasites alone did not lose weight or die (not shown).
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C) nor egg burden in the liver and gut (Fig. 1D) differed significantly between the two groups. In
contrast to this, significantly more eggs were recovered from the lungs
of infected CD154-/- mice than from WT mice
(Fig. 1E; p < 0.05). As might be expected
of this chronic infection, weight loss by
CD154-/- mice correlated with increasing liver
egg burden (not shown). Pathologic changes in target organs
Examination of gross pathology showed that splenomegaly, although
significant (p < 0.05), was less extreme in
infected CD154-/- mice than in infected WT mice
(Fig. 2A; p <
0.02). Pronounced hepatomegaly was evident in both groups of mice and
was not significantly different between infected groups (Fig. 2B). More detailed histopathological examination of
CD154-/- mice revealed several key differences
to similarly infected WT mice. Most notably, severe lung pathology was
evident in infected CD154-/- animals (Fig. 3). In the lungs, numerous focal
granulomas were found in CD154-/- (Fig. 3D), but not WT (Fig. 3C), mice, coincident with
increased numbers of ova and parasite debris in the lungs of these
animals. Although there was extensive inflammatory change in the lungs
of infected WT mice compared with uninfected controls, granulomas and
parasite debris were rare. Liver and gut pathology was similar in both
strains of mice, but fewer granulocytes and mature plasma cells were
observed in the absence of CD154 (not shown). Additionally, liver
granulomas were significantly reduced in size in infected
CD154-/- mice compared with WT mice (Fig. 3E; p < 0.001). Equivalent levels of
fibrosis were observed in both groups of infected mice by Masson’s
Trichrome staining (not shown).
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Adult S. mansoni typically reside within the mesenteric
veins of the murine host. To determine the role of CD40/CD154
interaction in development of the immune response during helminth
infection, we measured the in vitro production of signature Th2
cytokines IL-4, IL-5, and IL-13 by MLN cells isolated from infected
CD154-/- and WT animals (Fig. 4A). We also assessed in vitro
production of the proinflammatory Th1 cytokines, IL-12, TNF-, and
IFN-, and regulatory mediators, IL-10 and NO, in these cultures
(Fig. 4A). Compared with WT mice, MLN cells from infected
CD154-/- mice made significantly less IL-4,
IL-5, and IL-13 in response to SEA than those from infected WT mice
(p < 0.05). No significant difference in
levels of production of IL-12, TNF-, or IFN- was seen between the
groups, with each of these mediators being produced in low amounts.
Additionally, we measured levels of IL-10 and NO to determine whether
the reduced production of IL-4, IL-5, and IL-13 might be due to
enhanced levels of these regulatory mediators. However, this proved not
to be the case, with MLN from infected WT mice actually producing
significantly more Ag-specific IL-10 than those from
CD154-/- mice (p <
0.01), and with no significant difference between the groups in the
level of NO detected. Consistent with this, immunohistochemical
staining showed that there was no elevation in iNOS levels in lung,
liver, or gut from infected CD154-/- mice
compared with infected WT mice (not shown). Interestingly, MLN cells
from infected CD154-/- mice also showed an
impaired ability to produce IL-4, IL-5, and IL-13, but not IL-10,
IL-12, or NO in response to polyclonal stimulation with plate-bound
anti-CD3 mAb (not shown). Similar results were obtained from
splenocyte cultures stimulated with SEA or anti-CD3 (not
shown).
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were detected in splenocyte cultures from infected
CD154-/- mice at levels that did not differ
significantly from those in similarly infected WT mice (Fig. 4B).
We reasoned that the impaired Th2 cytokine production seen in vitro
might be due to the reduced initial numbers of cytokine-producing cells
or defective cellular proliferation in response to stimulation.
To determine whether either of these possibilities might be the case,
we examined the ability of MLN cells from WT or
CD154-/- mice to produce IL-4 and IFN- ex
vivo by ELISPOT (Fig. 5A) and to proliferate in
response to specific Ag (SEA; Fig. 5B) or to a mitogenic
stimulus (plate-bound anti-CD3; Fig. 5C) using CFSE.
Although no significant difference was seen in the number of freshly
isolated MLN cells that produced IL-4 or IFN- when obtained from
either WT or CD154-/- mice (Fig. 5A), the subsequent ability of these cells to proliferate
was somewhat impaired in CD154-/- animals (Fig. 5B). A reduction in the ability of MLN from infected
CD154-/- mice to proliferate was seen on
stimulation with SEA, but not with anti-CD3, compared with infected
WT mice. However, diminished Th2 cytokine production was apparent in
cultures exposed to both these stimuli (see above). Therefore, impaired
proliferation alone cannot account for the reduced ability of infected
CD154-/- mice to mount a Th2 response in vitro,
although it may contribute to the reduced Ag-specific response to SEA.
We have yet to determine whether the cells isolated from infected
CD154-/- mice that proliferate poorly to SEA
stimulation are T cells or B cells. The mechanism behind this defective
Ag-specific proliferation is not yet known, but is unlikely to be
effected by NO or IL-10, because levels of these mediators in culture
were not elevated in cells cultured from infected
CD154-/- mice compared with WT controls (see
above).
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To ensure that the impaired Th2 response observed in infected
CD154-/- mice in vitro was also apparent in
vivo, especially given the diminished Ag-specific proliferation we had
observed in vitro, we measured plasma levels of IL-4 and IL-5 by ELISA
(Fig. 6, A and B).
Supporting our in vitro data, levels of both IL-4 and IL-5 were
significantly less in infected CD154-/- mice
than in infected WT mice (p < 0.01 and
p < 0.03, respectively). A further indication of the
impaired ability of CD154-/- mice to mount a
Th2 response in vivo was illustrated by the significantly reduced
peripheral blood eosinophilia observed in infected
CD154-/- mice compared with WT mice (Fig. 6C; p < 0.001).
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). We measured plasma levels of
SEA-specific IgM, IgG1, and IgG2a and total levels of IgE. No elevated
IgE or IgG1, both of which are indicative of a Th2 response in mice,
were measured in infected CD154-/- mice. IgG2a,
which is indicative of IFN- production and Th1 response development
in mice, was not found in infected CD154-/-
animals and was found only at low levels in infected WT animals.
Parasite-specific IgM was measured in both groups of infected mice, but
was significantly less in CD154-/- than in WT
animals (p < 0.05).
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In many experimental systems CD40/CD154 has been shown to be
important for optimal activation of B cells (3). One
indicator of such activation is the level of MHC class II on the
surface of these cells. To determine whether CD40/CD154 interaction was
required for normal B cell activation in our system, we compared the
levels of expression of MHC class II on the surface of B cells
(B220+) and other APC
(Mac-1+ cells; Table I). B cells and other APC in infected
CD154-/- mice displayed significantly lower
levels of surface MHC class II than WT mice following infection with
S. mansoni, although they showed some up-regulation compared
with uninfected controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In light of the greatly reduced levels of Th2 cytokines in their plasma and that accumulate in culture supernatants of Ag- or aCD3-stimulated lymphoid organ cells of infected CD154-/- mice, it is interesting that the frequency of cells that can produce Th2 cytokine is equivalent in infected CD154-/- and WT mice as assessed by ELISPOT. This discrepancy may reflect a lower level of cytokine production by CD154-/- animals on a per cell basis. Alternatively, the impaired ability of cells isolated from CD154-/- mice to produce Th2 cytokines after in vitro culture may be due to a defect in the expansion or survival of responder cells after activation. Supportive of this, we have found that SEA-specific proliferation was reduced in CD154-/- animals compared with WT, and others have shown that T cell persistence as well as priming are defective when CD40/CD154 interaction is disrupted (21, 22). However, the reduced ability of CD154-/- mice to mount a Th2 response in vivo, characterized by reduced plasma IL-4, IL-5, IgG1, and IgE levels and reduced peripheral blood eosinophilia in these animals, suggests that our in vitro findings are physiologically relevant.
One interpretation of our data is that B cells play an important role in Th2 response induction, because in the absence of CD40/154 interaction, B cell responses are severely impaired (3). Our data indicate that B cells are not activated appropriately in CD154-/- mice during infection, showing reduced activation status in terms of MHC class II expression and defective isotype switching. Both these outcomes may at least in part be due to the reduced levels of IL-4 produced by infected CD154-/- mice, because IL-4 can act to induce MHC class II up-regulation and facilitate isotype switching to the production of IgE and IgG1 (23). Additionally, granuloma cellularity was somewhat different in infected CD154-/- mice, which had a reduced proportion of plasma cells compared with WT mice. The role of B cells in schistosomiasis is intriguing, but as yet not fully resolved. Somewhat conflicting reports have suggested that mice lacking B cells either fail to mount a Th2 response during infection (24) or mount a normal Th response but develop more severe disease, failing to regulate granulomatous pathology (25). Our data resemble the outcome of infection in B cell-deficient JH mice, in that they fail to mount a Th2 response, but also exhibit impaired granuloma formation and severe pathology. The emerging role of specific B cell subsets that secrete specific cytokines in immune response polarization (26) raises the interesting possibility that a defective B cell response may also directly influence the resultant cytokine profile during schistosome infection, a possibility that remains to be investigated.
DC represent another CD40-bearing cell type that can be activated through ligation by CD154 (3, 27, 28). It is possible that defective DC function could contribute to the impaired Th2 development we have observed in infected CD154-/- mice. Supportive of this hypothesis, we have shown that CD40-deficient, bone marrow-derived DC exhibit a diminished ability to induce Th2 responses in vivo (29). We have yet to investigate the activation status of DC isolated from S. mansoni infection in the absence of CD154. An additional possibility that remains to be addressed is whether signaling to the T cell via CD154 might directly drive Th2 development during infection (30, 31, 32).
Costimulation has previously been shown to be important for the
development of a Th2 response to S. mansoni infection, as
mice doubly deficient for both CD80 and CD86 fail to mount a Th2
response to the parasite (33). However, in this case the T
cell cytokine profile was reversed, with CD80/86-deficient mice
secreting higher levels of IFN- than WT mice coincident with the
loss of IL-4 production. This contrasts what we have seen during
infection of CD154-/- mice, where no such
compensatory Th1 response is noted on loss of the Th2 response.
Nevertheless, our data suggest that one outcome of CD40/CD154
interaction might be to initiate events that lead to up-regulation of
costimulatory molecules such as CD80 and CD86, although the low levels
of these molecules measured during infection of even WT mice has made
it difficult to show this experimentally (unpublished observations).
Nevertheless, it seems that the sequence of events that leads to Th2
response development originates with and is dependent upon CD40 and
CD154 interaction.
The rapid severe weight loss seen in infected
CD154-/- mice bears similarity to the outcome
of infection of IL-4-/- mice infected with
S. mansoni (19). In the case of
IL-4-/- mice, however, in the absence of Th2
response development an inflammatory response is observed,
characterized by elevated production of inflammatory mediators such as
NO and IFN-. This contrasts with what we have noted in infected
CD154-/- animals, in which no such elevated
inflammatory response is seen. It is difficult to address whether the
absence of CD154 might impair Th1 response development to S.
mansoni, because infection does not induce a marked Th1 response
even in WT mice. Thus, we cannot discount the possibility that infected
CD154-/- animals may also mount a defective Th1
response to the parasite.
An additional unexpected finding in infected CD154-/- mice was the presence of large numbers of eggs and severe pathologic changes in the lungs. This occurred before wk 8 of infection at a time when it is rare to find eggs in the lungs of WT mice. Shunting to the lungs reflects the development of portal hypertension and the formation of varices that allow blood to leave the portal system without passing through the liver. Eggs produced by the parasites in the portal system are thus able to pass through the venous system to the heart and be pumped on to the lungs where they become trapped in the capillaries. This indication that infected CD154-/- mice develop severe portal hypertension shortly after egg production begins suggests that there is a failure of vascular regulation in these animals. Infected WT mice exhibit low, but detectable, levels of iNOS in and around granulomas in the liver, gut, and lungs, but this is not seen in infected CD154-/- mice. Therefore, it is possible that reduced production of mediators such as NO in this context might result in defective vascular regulation, perhaps due to impaired vasodilation, that could, in turn, lead to more rapid development of portal hypertension and its detrimental sequelae.
It has previously been shown that IL-4 and IL-13 play important roles in granuloma formation and development of fibrosis during schistosome infection (11, 34). Interestingly, even in the face of a severely impaired Th2 response and a virtual absence of production of IL-4 and IL-13 to the parasite, infected CD154-/- mice did not show significantly different levels of fibrosis from those in WT mice. It is possible that the very low levels of these mediators measured in vitro might be sufficient to allow the development of fibrosis in vivo, or that other mediators are involved. Moreover, the fact that a granulomatous response was mounted by CD154-/- mice indicates that there is a CD4 T cell component in the response to infection by these animals (35).
In summary, our data show that CD40/CD154 interaction is required to allow Th2 response development to the parasitic helminth S. mansoni, and that the absence of this response has fatal consequences for the host. These novel observations have implications for understanding the underlying mechanisms of Th2 response initiation, highlighting the pathophysiological relevance of this receptor/ligand pair in this process, and may impact the development of future immunotherapeutic strategies for other Th2-dominated diseases.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6008.
3 Current address: Department of Comparative Biological Sciences, University of Wisconsin School of Veterinary Medicine, Madison, WI 53708.
4 Current address: Victoria University of Wellington School of Biological Sciences, Wellington, New Zealand.
5 Current address: Servico de Imunologia, Hospital Universitario Professor Edgard Santos, Universidade Federal da Bahia, Bahia, Brazil.
6 Address correspondence and reprint requests to Dr. Edward J. Pearce at the current address: 203D Johnson Pavilion, 3610 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104-6076. E-mail address: ejpearce{at}mail.med.upenn.edu
7 Abbreviations used in this paper: DC, dendritic cells; MLN, mesenteric lymph node; SEA, soluble egg Ag; STAg, soluble tachyzoite Ag; WT, wild type.
Received for publication November 16, 2001. Accepted for publication February 25, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is necessary but not sufficient for anti-CD40 Ab-mediated inhibition of the Th2 response to Schistosoma mansoni eggs. J. Immunol. 164:779.-independent IL-12. J. Immunol. 163:2081.-mediated cachexia and death during acute schistosomiasis. J. Immunol. 159:777.[Abstract]
production. Eur. J. Immunol. 26:1621.[Medline]
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) or SEA (
) for 72 h before supernatant
harvest. B, Cytokine production as measured by ELISA in
culture supernatants from spleen cells taken from uninfected (control)
or T. gondii-infected WT or CD154-/- mice.
Spleen cells were then stimulated in vitro with medium (
) for 72 h before supernatant harvest. Data shown are the
mean ± SD of triplicate wells from three to six mice per group
that were individually assayed.
