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* Institut National de la Santé et de la Recherche Médicale, Unité 547, Institut Pasteur de Lille, Lille, France;
Immunex, Seattle, WA 98101;
Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; and
Université Libre de Bruxelles, Gosselies, Belgium
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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 mice, peptide fragments are presented by MHC I and II molecules, whereas (glyco)lipids are preferentially presented via the CD1d molecule (17, 18). The later type of presentation is probably relevant during S. mansoni infection because glycosphingolipid structures are abundantly expressed by the eggs (12, 19, 20). Moreover, it has been recently shown that during human schistosomiasis, glycolipids from Schistosoma are the main targets for the IgE response, suggesting a role in the IgE-mediated host protective response (21). In this work, we show that DC selectively present glycosylated Ag from the egg stage of S. mansoni to polarize the immune response toward a specific Th2-biased response, and that the CD1d-restricted mode of Ag presentation plays a key role in this phenomenon. Finally, we provide evidence that CD1d is important for the generation of an optimal Th2 response and in the subsequent liver pathology that develops in infected mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c mice were purchased from Iffa-Credo (l’Arbesle, France). The generation of CD1d-deficient BALB/c mice has been described previously (22). CD1d knockout (KO) mice from the ninth backcross to BALB/c were used in this study.
Reagents and Abs
The purified anti-CD3 mAb and the biotin-conjugated anti-CD11c mAb were purchased from BD Biosciences (Le Pont de Claix, France). PE-streptavidin was from Clinisciences (Montrouge, France), and microbead-conjugated anti-CD11c mAb used for MACS purification were from Miltenyi Biotec (Paris, France). The murine anti-Lex mAb was from Immunotech (Marseille, France). The polyclonal rabbit serum directed against the S. mansoni 28-kDa protein (Sm28GST) has already been described (23). Mouse rGM-CSF was purchased from Biosource (Nivelles, Belgium). Human rFlt-3 ligand was provided by Immunex (Seattle, WA). The anti-CD1d mAb was purified from the 1B1 hybridoma supernatant (a gift from Dr. M. Kronenberg, La Jolla Institute for Allergy and Immunology, San Diego, CA) (24) using protein G-agarose columns (Life Technologies, Grand Island, NY). An irrelevant rat IgG2b mAb was used as a control.
Ag preparation and metaperiodate treatment
S. mansoni (Puerto Rican strain) schistosomula were obtained by the skin penetration procedure from cercariae shed from infected Biomphalaria glabrata snails (25). Eggs were obtained from the liver of infected golden hamsters after portal vein perfusion. Soluble skin schistosomulum Ag (SSA) and SEA were prepared as follows. Parasites or eggs were resuspended in cold PBS and sonicated (Misonix, Vasse, Templemars, France) 4 x 15 s at 4°C. The homogenates were then centrifuged twice at 13,000 x g for 20 min, dialyzed for 12 h against cold RPMI, passed twice through polymyxin columns, and sterile filtered. Protein concentration was determined by the bicinchoninic protein assay kit (Pierce, Rockford, IL). The absence of endotoxin in SSA and SEA was checked by performing a Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD). To alter the carbohydrate structures of SEA, egg Ag (2 mg/ml in a final concentration of 50 mM sodium acetate buffer, pH 4.6) was added to 10 mM sodium metaperiodate for 15 min, after which oxidation was stopped by adding a final concentration of 50 mM sodium borohydride (7). Mock-treated SEA was obtained by the same procedure, but with the omission of sodium metaperiodate. After treatment, mock- or periodate-treated SEA was extensively dialyzed against cold RPMI. For Western blot analysis, SEA was resolved on 10% SDS-polyacrylamide gels and electroblotted onto nitrocellulose membranes. Membranes were incubated overnight at 4°C with primary anti-Lex or anti-Sm28GST Abs diluted in PBS supplemented with 0.1% (v/v) Tween 20 and 5% (w/v) nonfat dried milk. After washing, membranes were incubated with HRP-labeled goat anti-mouse or anti-rabbit Ig (Sanofi Diagnostics Pasteur, Marnes, France) and processed for ECL detection (Amersham, Arlington Heights, IL).
Preparation and sensitization of DC
DC were isolated from spleens obtained from Flt-3 ligand-treated BALB/c mice, as already described (26). Briefly, spleens were digested with collagenase for 30 min at 37°C and then dissociated in HBSS containing 10 mM EDTA. The cell suspension was separated into low and high density fractions on a Nycodenz gradient (Nycomed Pharma, Oslo, Norway) (1700 x g for 15 min). Splenic DC were collected at the interface, washed twice with RPMI, and purified by positive selection over a MACS column by using microbead-conjugated anti-CD11c mAb. After purification, the cells were cultured in 100-mm petri dishes for 2 h at 37°C in RPMI supplemented with 2% ultroser (Life Technologies), a serum-free medium supplement. Nonadherent cells were removed by vigorous pipetting, and the adherent cells (immature DC) were allowed to mature for 18 h in RPMI supplemented with 2% ultroser and 10 ng/ml GM-CSF in the absence (unpulsed DC) or in the presence (pulsed DC) of 50 µg/ml Ag. In general, nonadherent mature DC represented at least 99% of the total cell population, as assessed by FACS analysis with anti-CD11c mAb.
Immunization protocol and analysis of the immune response
After overnight culture, nonadherent unpulsed or Ag-pulsed DC
were collected, washed, and administered at a dose of 3 x
105 cells into the hind footpads of syngenic
mice. In some cases, SEA-pulsed DC were treated for 1 h at 37°C
with 50 µg/ml anti-CD1d mAb (1B1) or isotype control mAb before
their transfer into recipient mice. Five days later, popliteal lymph
node (LN) cells (5 x 105 cells/well in
flat-bottom 96-well plate) were cultured in Click’s medium
supplemented with 0.5% normal mouse serum and various concentrations
of Ag for 4 days at 37°C. During the last 18 h, 0.5 µCi
[3H]thymidine/well was added. At the 72-h time
point, IFN-
, IL-4, IL-5, and IL-10 production was measured in the
culture supernatants from LN cells by ELISA. IL-4, IL-5, and IL-10 were
quantified by two-site ELISA adapted from BD PharMingen (San Diego, CA)
protocols (BD Biosciences). The supernatant was assayed for IFN-
using an ELISA kit from R&D Systems (Abingdon, U.K.).
Infection of mice and analysis of the parasitological and immunological parameters
Eight-week-old female wild-type (wt) and CD1d KO BALB/c mice
were percutaneously infected with 60 cercariae, and worm burdens were
measured by liver perfusion 49 days after infection (27).
At the time of perfusion, the small intestines and the livers were also
collected for measurement of egg numbers deposited in these organs.
Tissues were digested in 4% KOH, as previously described
(28). Records of the organ weights allowed the calculation
of total tissue eggs per organ. For the kinetic study, spleens were
harvested at days 31, 49, and 63 postinfection, and cells were
stimulated with anti-CD3 Ab (5 µg/ml), to allow the stimulation
of all in vivo (pre)activated cells, for 3 days at 37°C. During the
last 18 h, 0.5 µCi [3H]thymidine/well
was added. At 48-h time point, IFN-, IL-4, IL-5, and IL-13
production was measured in the culture supernatants. To study the
humoral response, mice were bled 49 days after the infection, and the
anti-SEA IgG1 and IgG2a titrations were determined for each mouse
by ELISA. Briefly, flat-bottom 96-well plates (Maxisorp; Nunc,
Roskilde, Denmark) were coated overnight with 10 µg SEA in PBS
at 4°C. After washing with PBS/0.1% Tween 20 (PBS/Tween), plates
were incubated with PBS/0.5% gelatin for 1 h. Serum samples were
serially diluted 1/2 (starting at 1/100 for IgG2a and 1/10,000 for IgG1
titrations) in PBS/Tween and incubated overnight at 4°C. After
washing, HRP-conjugated anti-mouse IgG2a or anti-IgG1 was added
to each well for another 2 h. Enzymatic activity was detected with
3,3',5,5'-tetramethylbenzidine substrate and stopped with 2 N HCl. The
absorbancies were read at 450 nm on a Titertek Multiskan. Serum titers
are defined as the dilution that gives an OD reading at least 2-fold
higher than the mean background of noninfected mouse serum, and results
are expressed as IgG1-IgG2a serum titer ratio.
Analysis of the egg-associated liver pathology in infected mice
The egg-associated pathology was analyzed on the livers of mice 49 days after the infection (20–23 mice per group) in a double blind fashion. Briefly, a small piece of liver from each mouse was fixed in acetic acid-based fixative for 2–3 days and embedded in paraffin. Then, 4-µm liver sections were stained with either H&E for granuloma diameter measurement or May Grunwald Giemsa for eosinophilia examination. The diameters and eosinophil contents of granulomas (10/mouse) surrounding single, mature, and viable eggs were measured using the Metaview computing software (Roper Scientific, Evry, France), and the volume of each granuloma was calculated assuming a spherical shape. The degree of necrosis, visualized on H&E-stained sections, was quantified using an arbitrary scale from 0 (no necrosis) to 2 (severe liver necrosis). To visualize collagen deposition, liver sections were stained with Sirius red. Collagen deposition in granulomas (10–18/mouse) was quantified using an arbitrary scale from 0 (no collagen deposition) to 3 (strong collagen deposition all over the granuloma).
Statistical analysis
The statistical significance of differences between experimental groups was calculated using the Student’s t test. Values of p < 0.05 were considered as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using DC as APC, we first compared the nature of the T cell
response induced by larval (SSA) or egg (SEA) Ag. To this end, mice
were immunized in the hind footpads with 3 x
105 SSA- or SEA-pulsed DC (or unpulsed DC as a
control), after which popliteal LNs were harvested 5 days later and
restimulated in vitro with SSA or SEA, respectively. As shown in Fig. 1
, administration of DC sensitized ex
vivo with SSA or with SEA resulted in identical levels of T cell
priming, as determined by Ag-dependent proliferation in culture. We
next analyzed the cytokines released by LN cells primed with the
different DC preparations. As depicted in Fig. 1, SSA-pulsed DC induced
the activation of cells secreting IFN-, IL-4, IL-5, and IL-10
following restimulation with the same Ag in vitro. SEA-pulsed DC
sensitized cells to produce higher amounts of IL-4, IL-5, and IL-10,
and less IFN-. This experiment shows that, when captured, processed,
and presented to T lymphocytes by DC, both schistosome larval and egg
Ag induce the development of a specific mixed response, with the latter
skewing the cytokine profile toward a more Th2-like response.
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Because glycoconjugates from SEA are important targets for Th2
responses in vivo (7), we determined whether, when
presented by DC, carbohydrates on SEA are the main inducers of Th2
responses in our model of immunization. For this purpose, mild
periodate oxidation was performed, and the ability of the
periodate-treated SEA preparation to induce Th2 responses was analyzed.
We first validated the method of periodate treatment by analyzing the
antigenic preparations by Western blotting using specific Abs directed
against schistosome carbohydrate (anti-Lex
Ab) or peptide (anti-Sm28GST Ab) epitopes. As seen in Fig. 2A, the
anti-Lex Ab was reactive with untreated and
mock SEA, but not with periodate-treated SEA. Conversely, the
monospecific anti-protein Ab revealed a unique band in all
preparations (with an identical intensity). This experiment thus
confirmed that the periodate treatment altered the glycan moiety and
appeared to preserve the antigenic integrity of SEA.
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B shows, LN cells from mice
injected with DC pulsed with either mock- or periodate-treated SEA
proliferate in a similar manner and produce equal quantities of IFN-
in response to SEA. In contrast, the production of Th2 cytokines was
dramatically reduced (6- to 10-fold) in mice that received
periodate-treated SEA-pulsed DC. This indicates that, in our model of
immunization, the sugar moiety of SEA is particularly important in
generating specific Th2 immune response. CD1d is involved in Th2 immune responses induced by SEA-pulsed DC
Because glycolipid structures are abundant in S.
mansoni eggs (12, 19, 20), we evaluated the
contribution of CD1d, a molecule known to capture and present microbial
and self (glyco)lipid Ag to T cells (17, 18), to
Th2-biased response induced by SEA-sensitized DC. To this end,
SEA-pulsed DC were treated with a neutralizing anti-CD1d mAb before
their transfer into recipient mice and, 5 days later, LN cells were
restimulated in vitro with SEA. As Fig. 3A shows, LN cells from mice
injected with DC treated with either the anti-CD1d or isotype
control Ab proliferate in a similar manner and produce equal quantities
of IFN- in response to SEA. In contrast, the production of Th2
cytokines was dramatically reduced in mice that received DC treated
with the anti-CD1d Ab. This indicates that the availability of CD1d
on SEA-pulsed DC is particularly important in generating specific Th2
immune response. To confirm this, spleen DC were purified from wt or
CD1d KO mice, pulsed with SEA, and then injected into wt mice. Fig. 3B shows that administration of wt or CD1d KO-pulsed DC
resulted in comparable T cell priming, as assessed by SEA-dependent
proliferation of LN cells in culture. However, cytokine released into
the supernatants of these cultures differed dramatically because CD1d
KO-pulsed DC induced the activation of cells that secrete IFN-, but
little IL-4, IL-5, and IL-10. These results suggest that the
CD1d-restricted Ag presentation is crucial in the priming of
SEA-specific Th2 lymphocytes.
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We then studied the involvement of CD1d in the induction of Th2
responses to egg Ag in S. mansoni-infected mice. We first
analyzed the parasitological parameters in wt and CD1d KO-infected
mice, 49 days after infection. As shown in Table I, worm burdens as well as tissue (liver
and intestine) egg numbers were similar in the two animal groups,
indicating that the lack of CD1d does not influence parasite survival
and fecundity in infected mice. We then determined the titers of
SEA-specific IgG1 (a marker of a Th2 response) and IgG2a (a marker of a
Th1 response) in infected mice, 49 days postinfection. Although the
overall Ig levels were identical in both groups (not shown), the
average IgG1-IgG2a ratio was dramatically reduced in CD1d KO mice
(22 ± 10) compared with that of wt mice (76 ± 20) (66%
reduction) (Fig. 4). This suggests that
CD1d is important in the Th2 bias of SEA-reactive T cells and in the
subsequent generation of egg Ag-specific Th2-associated Ab isotypes
during infection.
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As mentioned in the introduction, the immune response in infected
mice switches from a Th1 to a Th2 response after egg laying. To know
whether infected CD1d KO mice failed to switch the immune response
after egg deposition, spleens were removed on day 31 (before egg laying
when the Th1 response prevails) and on days 49 and 63 (when egg-driven
Th2 responses predominate), and cells were restimulated with
anti-CD3. As represented in Fig. 5, IFN- production gradually declined in CD3-stimulated cells from wt,
as well as from CD1d KO-infected mice. In contrast, IL-4 and IL-5
production increased with the time of infection, but in a less marked
manner in CD1d KO-infected mice compared with wt mice. Similarly, the
synthesis of IL-13, a cytokine known to be important in fibrosis, was
dramatically reduced in CD1d KO mice compared with wt mice. This
indicates that CD1d deficiency does not appear to alter the capacity of
mice to down-regulate Th1 responses during infection, but affects, in a
significant manner, their ability to up-regulate the production of Th2
cytokines.
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Because the development of the Th2 response is important in the
egg-induced pathology in mice (29), we then proceeded to
evaluate the influence of CD1d on the formation of liver granuloma
during murine experimental schistosomiasis. To this end, livers were
examined histologically 49 days after the infection. In both animal
groups, the size of the granulomas
surrounding eggs was not statistically different (Table II). Compared
with wt mice (Fig. 6, A and
C), granulomas from CD1d KO-infected mice appeared less
cellular (Fig. 6B) and contained a reduced number of
eosinophils (Fig. 6D) (30% reduction, Table II). Because
fibrosis is a sequel to egg granuloma formation during infection, we
then visualized collagen deposition within the liver. Sirius red
staining demonstrated a dramatic decrease in collagenous material (red
stain) in the granulomas of CD1d KO animals (Fig. 6F)
compared with control mice (Fig. 6E). Quantitative studies
were conducted by scoring the sections using well-defined criteria for
degree of collagen deposition and necrosis. As Table II shows, CD1d
deficiency resulted in a reduction of collagen deposition in granulomas
(40%) and of necrosis (60%) in the livers of S.
mansoni-infected mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first compared the nature of the T cell response induced by larval
or egg Ag-pulsed DC in recipient mice. Our results show that when
captured and presented to naive T cells by DC, larval Ag induce a mixed
response, whereas, in agreement with a recent report (30),
SEA-pulsed DC skew the immune response toward a Th2 response, although
significant levels of IFN- are still produced. This correlation
between immune response profile and the infectious stage of the
pathogen has already been reported in the case of the fungus
Candida albicans (31), and is a likely
consequence of the high antigenic diversity between S.
mansoni schistosomula and eggs. We then investigated the role of
egg glycan structures in this phenomenon. We show that modification of
the structures of SEA carbohydrates sensitive to mild periodate
oxidation abolished the ability of pulsed DC to induce a specific Th2
response. Numerous studies have revealed that eggs contain large
amounts of highly antigenic N- and O-linked
proteins as well as lipid-associated glycoconjugates (12, 19, 20). Consequently, as a next step, we studied the impact of CD1d
neutralization or CD1d deficiency on the immune response after
immunization with SEA-pulsed DC. In this model, we found that ex vivo
blockade of CD1d availability (Fig. 3A) or CD1d deficiency
on DC (Fig. 3B) affects the priming of SEA-specific Th2
lymphocytes in recipient mice. At present, the presentation of
microbial glycolipids to T cells by the CD1d molecule is still
controversial. However, our findings suggest that the CD1d mode of Ag
presentation may be crucial in amplifying egg Ag-specific Th2
responses. It is therefore possible that SEA, or processed forms of
these Ag, directly bind with CD1d molecules and activate
CD1d-restricted T cells, particularly NK T cells. In this regard, it is
noteworthy that SEA contain a majority of saline soluble Ag and no, or
few, lipophilic Ag. This suggests that the structures in SEA presented
by CD1d probably possess amphiphatic properties. Preliminary results,
based on the fractionation of SEA according to lipophilic properties,
suggest that this is indeed the case. Attempts to identify the Ag
candidate(s) are underway at the moment. An alternative explanation for
our findings is that SEA may induce the expression of endogenous
glycolipid Ag that, in turn, bind with CD1d molecules and activate NKT
cells. There is significant evidence that NKT cells recognize self Ag
(17, 32, 33, 34, 35), which may be induced by stress and/or
pathogen-derived products. Future experiments will be aimed at
deciphering the precise role of the CD1d Ag presentation pathway in the
ability of SEA to promote Th2 responses.
We then investigated the impact of CD1d deficiency on the immune response and on granuloma formation during infection. Analysis of the humoral response revealed that the production of the Th2-associated Ab isotypes IgG1 and IgE (analyzed at day 63; not shown) was dramatically reduced in infected CD1d KO mice compared with wt mice. Moreover, but in a less marked fashion, the Th2 cellular response (as assessed by IL-4, IL-5, and IL-13 production) was also diminished, but not abrogated, in CD1d KO mice. This suggests that CD1d plays a role in the priming of Th2 cells specific for SEA in vivo. Because the Th1 to Th2 switch is important in the formation of granulomas in infected mice, we studied the effect of CD1d deficiency on egg-induced pathology in the liver. The size of granulomas surrounding eggs of CD1d KO mice was identical with those of granulomas in control infected animals. However, compared with wt mice, the intragranuloma cellularity was reduced in CD1d KO mice. Interestingly, the number of eosinophils, a cell population that is driven by Th2 cytokines and that is important in the immunopathology during murine schistosomiasis (36), was significantly diminished in CD1d KO mice. In these mice, we also observed a strong reduction in collagen deposition in the livers, a marker of liver fibrosis, and also a decrease in intra- and extragranuloma necrosis. Taken together, these findings suggest that CD1d deficiency results in a less marked hepatic pathology in S. mansoni-infected mice.
The involvement of CD1d in the induction of the SEA-specific Th2
response in DC injected as well as in S. mansoni-infected
mice strongly suggests a role for CD1d-restricted NKT cells in this
process. These cells are believed to play important functions in innate
and adaptive immune responses during infection (33, 35, 37), including parasite infection (38), and also
have been shown to be important players in some Th2-associated
responses (32, 34, 39). Recently, Brown et al.
(40), using a model of synchronous formation of pulmonary
granulomas elicited by injected S. mansoni eggs, suggested
that 
2-microglobulin-dependent T cells,
including NKT cells, play a minor role in the Th2 granulomatous
response in C57BL/6 mice. This apparently conflicting result can be
explained: 1) by the fact that in
2-microglobulin-deficient mice a residual
population of CD1d-restricted T cells remains, and 2) by differences in
the mouse strain (C57BL/6 vs BALB/c) or in the protocol used to induce
and to study granuloma formation (synchronous lung granulomas vs
nonsynchronous liver granulomas). Taken together, we speculate that, in
our model of immunization as well as during infection, CD1d-restricted
NKT cells may be important cellular components in the early events,
leading to the activation of MHC class II-restricted SEA-specific Th2
cells, for instance by rapidly secreting large amounts of IL-4 after
their activation. Interestingly, a recent study suggests that certain
glycolipid structures are indeed capable of inducing a predominant
production of IL-4 (but not IFN-) by CD1d-restricted NKT
(41). At the moment, we are studying the kinetics of NKT
cell activation in vivo after DC injection as well as during murine
infection, particularly in the liver, an organ known to be rich in NKT
cells.
To conclude, our data suggest that the CD1d-restricted presentation of egg glycoconjugates plays an important role in the induction of Th2 responses during murine schistosomiasis, and underline the possible involvement of CD1d-restricted T cells in the early immunological events leading to the egg-associated pathology in infected mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. François Trottein, Institut National de la Santé et de la Recherche Médicale, Unité 547, Institut Pasteur de Lille, 1, rue du Professeur Calmette, BP 245, 59019 Lille cédex, France. E-mail address: Francois.Trottein{at}pasteur-lille.fr
3 Abbreviations used in this paper: SEA, soluble egg Ag; DC, dendritic cell; KO, knockout; Lex, Lewis X; LN, lymph node; Sm28GST, S. mansoni 28-kDa protein; SSA, soluble schistosomula Ag; wt, wild type.
Received for publication October 19, 2001. Accepted for publication April 29, 2002.
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  L. Breuilh, F. Vanhoutte, J. Fontaine, C. M. W. van Stijn, I. Tillie-Leblond, M. Capron, C. Faveeuw, T. Jouault, I. van Die, P. Gosset, et al. Galectin-3 Modulates Immune and Inflammatory Responses during Helminthic Infection: Impact of Galectin-3 Deficiency on the Functions of Dendritic Cells Infect. Immun., November 1, 2007; 75(11): 5148 - 5157. [Abstract] [Full Text] [PDF]
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T. Mallevaey, J. Fontaine, L. Breuilh, C. Paget, A. Castro-Keller, C. Vendeville, M. Capron, M. Leite-de-Moraes, F. Trottein, and C. Faveeuw Invariant and Noninvariant Natural Killer T Cells Exert Opposite Regulatory Functions on the Immune Response during Murine Schistosomiasis Infect. Immun., May 1, 2007; 75(5): 2171 - 2180. [Abstract] [Full Text] [PDF]
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C. M. Kane, L. Cervi, J. Sun, A. S. McKee, K. S. Masek, S. Shapira, C. A. Hunter, and E. J. Pearce Helminth Antigens Modulate TLR-Initiated Dendritic Cell Activation J. Immunol., December 15, 2004; 173(12): 7454 - 7461. [Abstract] [Full Text] [PDF]
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V. V. Parekh, A. K. Singh, M. T. Wilson, D. Olivares-Villagomez, J. S. Bezbradica, H. Inazawa, H. Ehara, T. Sakai, I. Serizawa, L. Wu, et al. Quantitative and Qualitative Differences in the In Vivo Response of NKT Cells to Distinct {alpha}- and {beta}-Anomeric Glycolipids J. Immunol., September 15, 2004; 173(6): 3693 - 3706. [Abstract] [Full Text] [PDF]
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