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Production Within the Granulomas of Murine Schistosomiasis in IL-4-Deficient and Control Mice1
Departments of
*
Internal Medicine and
Pathology, Divisions of Gastroenterology-Hepatology and Allergy, University of Iowa, Iowa City, IA 52242
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and show no Th1 polarization. This could signify
that these granulomas have few cells capable of IFN- synthesis or
that such cells are under tight control. Granulomas can make IL-10 and
TGF-ß, which can regulate IFN- synthesis. Using FACS analysis and
ELISA, we explored the origin and regulation of IFN- in schistosome
granulomas from both IL-4-/- and
IL-4+/+ mice. FACS analysis of intracytoplasmic IFN-
staining showed that some granuloma Thy1.2+ T cells
(CD8+ and CD4+) express IFN-. Granulomas had
NK1.1+ cells, but they appeared to produce little or no
IFN-. Purified granuloma Thy1.2+ cells made IFN- in
vitro, whereas isolated NK1.1+ lymphocytes secreted little
even with rIL-12 stimulation. Culture of granuloma cells with blocking
anti-IL-10 or anti-TGF-ß mAb or with rIL-12 substantially
increased T cell IFN- synthesis, particularly in the
IL-4-/- animals. Cultured granuloma cells depleted of
Thy1.2+ lymphocytes by Ab and C released no IFN-. It is
concluded that granuloma IFN- comes from T cells, not NK cells.
Also, this T cell-derived IFN- is subject to IL-10 and TGF-ß
regulation, which is particularly evident in IL-4-/-
mice. Thus, the Th2 granuloma of schistosomiasis has large numbers of
activated Th1 or Th0 lymphocytes that are under tight restraint. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Some studies suggest that IL-4 is critical for preventing Th1
expression during natural infection. For instance, in murine
Leishmania major infection, the level of IL-4 at the time of
infection can significantly affect the Th cell phenotype and disease
outcome (2). IL-4 can oppose Th1 cell development during an immune
response (3). Yet, in the absence of IL-4, schistosome liver granulomas
make little IFN- and lacked features of the Th1 phenotype. This
indicated that the production of IL-4 early in the inflammatory process
is not the only mechanism limiting the development of a Th1 response in
schistosomiasis.
This finding prompted the current experiments, which further explore
both the origins and regulation of IFN- in the liver granulomas of
IL-4-/- and IL-4+/+ animals infected with
schistosomiasis. Our detailed analysis showed that granuloma IFN-
mostly comes from 
ß T cells that are subject to IL-10, TGF-ß,
and IL-12 regulation within this Th2-type inflammation. IL-10 and
TGF-ß appear to work synergistically. The influence of these
immunoregulatory cytokines is more evident in the IL-4-/-
mice. Our data provide the first evidence that the strong Th2-type
schistosome granuloma in the liver of naturally infected animals
contains Th1 or Th0 cells, which are under tight control.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study used female C57BL/6 IL-4-/- and littermate controls (IL-4+/+). IL-4-deficient mice were generated as previously described (4). At 7 to 8 wk of age, mice were infected s.c. with 50 cercariae of the Puerto Rican strain of Schistosoma mansoni (5, 6).
Dispersal of granuloma cells and splenocytes, and cell culture
Livers of mice killed during the 8 wk of infection were homogenized for 30 s at low speed in a Waring blender. Granulomas were collected by 1 x g sedimentation and washed three times in RPMI 1640 medium. To prepare a single cell suspension from these granulomas, the intact granulomas were incubated in a shaking water bath at 37°C for 30 min in RPMI 1640 medium containing 0.5% collagenase (type 1 from Clostridium histolyticum, Sigma, St. Louis, MO). The softened granulomas were disrupted further by repeated suction and expulsion through a 1-ml syringe. The dispersed granuloma cell suspensions were passed through a sterile gauze to exclude nondispersed fragments. The cells were collected by centrifugation, washed three times in RPMI 1640 medium, and counted. Cell viability was determined by trypan blue exclusion.
Single cell suspensions of splenocytes were prepared from individual spleens from 8-wk-infected or uninfected mice by gentle teasing in RPMI 1640 medium. The cells were briefly resuspended in distilled water to lyse RBC. The splenocytes then were washed three times in a large volume of RPMI 1640 medium.
Cells were cultured in 96-well microtiter plates with 200 µl of
medium (106 cells/well) at 37°C. Some cells were cultured
for 18 h to collect supernatant for cytokine measurement by ELISA.
Other cells were maintained in culture for either 1 or 18 h before
monensin A exposure and intracytoplasmic IFN- analysis. The culture
medium was RPMI containing 10% FCS, 10 mM HEPES buffer, 2 mM
L-glutamine, 100 U/ml penicillin, 5 µg/ml gentamicin, and
100 µg/ml streptomycin (all from Sigma). The cells were cultured
alone or in the presence of
SEA.3 The SEA was kindly
provided by the United Nations Development Programme/World Bank/World
Health Organization Special Program for Research and Training in
Tropical Diseases. Some cultures also contained blocking IL-10 (SXC-2,
American Type Culture Collection, Rockville, MD) and/or blocking
TGF-ß (Genentech, San Francisco, CA) mAb or appropriate isotype
control. Our cultures received rIL-12 (Genetics Institute, Cambridge,
MA). The anti-CD3 (145.2C11, provided by Jeffrey Bluestone,
University of Chicago) was used at 1 µg/ml. The culture supernatants
were assayed for IFN- fresh or briefly stored at -70°C before
assay.
T cell deletion
To lyse T cells, splenocytes or granuloma cells (2 x 106/ml) were incubated for 1 h at 4°C in RPMI 1640 medium containing monoclonal anti-Thy1.2 (Accurate, Westbury, NY) at the appropriate concentration. Control cells were treated with comparable dilutions of normal mouse serum (NMS). After incubation, the cells were washed by centrifugation at 4°C, suspended in an equal volume of a 1/10 dilution of Low-Tox-M rabbit C (Accurate), and incubated again for 1 h at 37°C. Next, the cells were again treated with Ab and C as described above. After washing in RPMI 1640 medium, viability was determined with eosin-Y. Anti-Thy1.2 successfully depleted the T cell population as determined by FACS analysis.
IFN- ELISA
The IFN- concentration in supernatants was measured by
two-sandwich ELISA. Plates were coated with mAb HB170 to IFN-
(American Type Culture Collection) and incubated with supernatant.
IFN- was detected with polyclonal rabbit anti-IFN- followed
by biotinylated goat anti-rabbit IgG (Accurate),
streptavidin-horseradish peroxidase and ABTS substrate (Zymed, San
Francisco, CA). The sensitivity of the ELISA was 30 pg/ml. The IL-4,
IL-5, and IL-10 ELISAs were performed as previously described (1). The
TGF-ß ELISA used mAbs from R&D Systems (Minneapolis, MN).
Other mAbs
FITC-labeled GK1.5 (anti-CD4), FITC- or Cy5–30-H12
(anti-Thy1.2), FITC-145-2C11 (anti-CD3), PE-GL3
(anti-
-TCR), PE-PK136 (anti-NK1.1), and PE-53-6.7
(anti-CD8a) Abs were purchased from PharMingen (San Diego, CA).
Unlabeled XMG 1.2 (anti-IFN-) Ab was provided by Dr. Jackie
Chace (University of Iowa) and cyanilated by Fluorolink Cy5 reactive
dye (Biologic Detection Systems, Pittsburgh, PA) according to the
recommendations of the manufacturer.
Flow cytometry
For three-color analysis, cells in HBSS containing 10% bovine
calf serum, 10 mM HEPES, and 0.02% NaN3 at
107/ml were stained with saturating amounts of labeled Abs
(2.5–5 µg/ml) on ice for 30 min in a 50-µl volume in the presence
of 2.4G2 mAb to inhibit FcR-mediated binding. Following the
incubation step with Abs, the cells were washed three times. To
determine the level of nonspecific binding, control cells were
incubated with isotype-matched Ab.
For intracellular cytokine staining, the cells were incubated in
complete medium in the presence of 10 ng/ml PMA, 1 µM ionomycin, and
2 µM monensin A for 5 h at 37°C, than stained for surface Ags
as outlined above. After staining, the samples were fixed overnight at
4°C with 2% paraformaldehyde-PBS solution. Having removed the
fixative, the cells were washed in FACS washing buffer and
permeabilized with Fix & Perm permeabilization medium (Caltag, San
Francisco, CA) for 15 min at room temperature. The cells then were
incubated in the presence of 2.5 µg/ml fluorochrome-labeled
anti-IFN- mAb for 15 min at room temperature and washed three
times. To determine nonspecific binding by the anti-IFN- Ab,
each experiment contained control cell samples that were incubated in
the presence of rIFN- (Sigma). The range of IFN-+
cells after cold IFN- blocking was 1.2 to 1.6% of the Thy1.2
population.
Statistical analysis
Statistical analysis was performed using Student’s t test for the paired case.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in granulomas
It was previously shown that dispersed granuloma cells from normal
C57BL/6 mice cultured in vitro will release small amounts of IFN-
(1). Moreover, IL-4-deficient C57BL/6 mice produce somewhat more
IFN-. NK cells as well as + and
ß+ lymphocytes are potential sources of IFN-. Using
FACS analysis and ELISA, we explored the origins of IFN- in
schistosome granulomas from both IL-4-/- and
IL-4+/+ mice.
Flow cytometric analysis showed that dispersed granuloma cells from
IL-4-/- animals have Thy1.2+ and
NK1.1+ lymphocytes (Fig. 1
).
They comprised 30.6 ± 6 and 3.4 ± 0.5% of the total
granuloma cell population located in the lymphoid gate (±SE;
n = 4). Although the majority of the NK1.1+
cells were CD3- and Thy1.2low/-, a
significant number were NK1.1+, CD3+, and
Thy1.2+. Analysis of freshly isolated granuloma cells by
intracellular staining revealed that 4.2 ± 0.9% (±SE;
n = 4) of Thy1.2+ cells were producing
IFN-. Surprisingly, essentially no NK1.1+ cells or
+ T cells stained for intracellular IFN- (<1%;
n = 3; Fig. 2).
Granulomas contained CD4+ and CD8+ T cells at a
ratio of about 2:1. Also, a substantially higher proportion of
CD4+ than CD8+ T cells expressed IFN- (Fig. 3).
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staining exclusively in the
Thy1.2+ T cell subset. In contrast to IL-4-deficient mice,
littermate controls had fewer IFN-+ cells; 2.0 ±
0.7% of Thy1.2+ cells stained for intracellular IFN-
(±SE; n = 4; Fig. 4).
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production
IL-4-/- mice do not form polarized Th1
granulomas. Rather, they produce limited amounts of IFN-. The low
level of IFN- emanating from IL-4-deficient mouse granuloma cells
could signify that these granulomas have few cells capable of IFN-
synthesis or that such cells are under tight control. Granulomas make
many cytokines, such as IL-10 and TGF-ß, which can regulate IFN-
synthesis. We tested whether IL-10 or TGF-ß were restraining IFN-
production in schistosome granulomas.
IL-12 is a cytokine that can stimulation IFN- production. Therefore,
we also determined whether IL-12 could induce IFN- in granuloma T
and NK cells.
Granuloma cells from IL-4-deficient mice cultured in vitro for as
little as 18 h in the presence of neutralizing anti-IL-10 mAb,
anti-TGF-ß mAb, or rIL-12 secreted substantially more IFN-
than cells cultured alone (Table I).
Isotype control mAbs had no effect. Cells exposed to both
anti-IL-10 and anti-TGF-ß mAbs made IFN- in amounts
similar to cells receiving either treatment alone. Flow cytometric
analysis showed that overnight incubation elevated the frequency of the
IFN-+ cells in the Thy1.2 population 7.0 ± 0.8%
(±SE; n = 4). Blockade of either IL-10 or TGF-ß or
stimulation with rIL-12 further enhanced the number of cells expressing
IFN- in the Thy1.2+ lymphocyte subset (Fig. 5 and Table II). Few NK1.1+ cells (Fig. 5) and no + T cells made IFN- even with cytokine
blockade or rIL-12 stimulation.
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in response to anti-IL-10 mAb,
anti-TGF-ß mAb, or rIL-12 (Table I
). This more modest response
also was evident in the Thy1.2+ T cell subset by flow
cytometry (data not shown).
Since culturing granuloma cells with neutralizing anti-IL-10 or
-TGF-ß mAb substantially increased IFN- production, we determined
whether these cells released substantial amounts of these
immunoregulatory cytokines. As shown in Table III, granuloma cells from
IL-4-/- and IL-4+/+ controls secreted large
amounts of IL-10 and TGF-ß. However, the granuloma cells from IL-4
mutant mice made much more IL-10 than did cells from the wild-type
controls.
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Ag-induced IFN- production
When granuloma cells from IL-4-/- or
IL-4+/+ mice were incubated with SEA (5 µg/ml) for
18 h in vitro, they secreted more IFN- (Table I). This increase
in IFN- production was not evident by flow cytometric analysis. FACS
data did not show an increase in the frequency of IFN--producing
Thy1.2+ T cells (data not shown). NK cells and
+ T cells again did not stain.
Granuloma NK cells do not release IFN-
Since dispersed granuloma cells contained few
NK1.1+ cells, it is possible that small numbers of
granuloma NK1.1+ cells did make IFN-, but were not seen
because of a limitation in the sensitivity of FACS analysis of
intracytoplasmic cytokines. Therefore, we isolated granuloma NK cells
(NK1.1+) to 99% homogeneity by FACS sorting. These
isolated cells then were cultured in vitro for up to 48 h in the
presence or the absence of rIL-12 or adherent anti-CD3. No IFN-
was detected in culture supernatants of FACS-purified granuloma NK
cells. Thy1.2+ T cells isolated similarly made IFN-
constitutively and in a greater amount in response to rIL-12 or
adherent anti-CD3 (Table IV). Splenic
NK cells from normal mice responded to rIL-12.
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secretion is T cell dependent
Granuloma T cells from IL-4-deficient mice were depleted by immune
lysis with anti-Thy1.2 and rabbit C to further characterize the
importance of T cells in granuloma IFN- production. Flow cytometry
confirmed that such treatment depleted about 95% of the
Thy1.2+ lymphocytes. As expected, granuloma cells
treated with NMS and C and cultured in vitro for 18 h still
released IFN- constitutively. IFN- production remained highly
responsive to rIL-12 and anti-IL-10 mAb treatment. However,
granuloma cells treated with anti-Thy1.2 and C failed to release
IFN- constitutively and responded only weakly to rIL-12 or to IL-10
blockade. This suggested that most granuloma IFN- production was
dependent upon the presence of T cells (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
The C57BL/6 IL-4-/- mouse confirmed the importance
of IL-4. Yet, in the IL-4-/- animals, schistosome
granulomas forming in the liver during natural infection do not produce
much IFN- and fail to show features of Th1-type inflammation (1).
This project had two objectives. The first was to determine the origin
of IFN- within these schistosome granulomas, and the second was to
ascertain why there was little IFN- emanating from these
lesions.
CD4+ T lymphocytes, CD8+ T lymphocytes, and NK
cells probably are the major sources of IFN- at sites of
inflammation. The granulomas of the IL-4-/- and
IL-4+/+ animals had all these cell types, although
CD4+ T cells were the most numerous subset.
Intracytoplasmic staining for IFN- suggested that CD4+
and CD8+ T cells were the sources of IFN- within the
granulomas of either animal. Both positive and negative cell selection
experiments also indicated that T cells, not NK cells, were the origin
of IFN-. Granuloma cells from IL-4-/- animals secrete
somewhat more IFN- than cells from littermate controls. Flow
cytometric analysis also supported this observation by showing that a
larger percentage of the granuloma T cells from IL-4 mutant mice made
IFN-. The granulomas also had T cells that were
CD4- CD8- (1). These cells did not appear to
make IFN-.
Classical NK cells, which display NK1.1 Ag, do not express TCR and can
produce high levels of IFN-. There also is a novel T cell population
expressing the NK1.1 molecule. They can produce large amounts of IL-4
and possibly IFN-. Most granuloma NK1.1+ cells were
CD3- and Thy1.2low/-, suggesting that many
were conventional NK cells. Yet, there was a sizable number of NK T
cells, as evidenced by expression of CD3. IL-12, IL-2, and signaling
via the NKR-P1 receptor (7) can induce IFN- release from both NK
cells and NK1.1+ T cells. The mechanism limiting IFN-
production from granuloma NK cells remains unknown.
Schistosomiasis is a parasitic disease in which ova deposit in the
liver, intestines, and, at times, other organs. Dispersed granuloma
cells from livers of naturally infected C57BL/6 mice constitutively
secrete the Th2 cytokines IL-4, IL-5, and IL-10. Thus, it was an
unsuspected finding that granuloma cells of IL-4+/+ mice
contained T cells that made IFN- constitutively.
In murine schistosomiasis, experiments using purified CD8+
or CD4+ splenic T cell subsets showed that CD8+
T cells can be a major source of IFN- when incubated with rIL-2 or
rIL-4 and plate-adherent anti-CD3. These data suggested that
schistosomiasis promotes the development of a strong type 1
CD8+ T cell response (8). It also is postulated that type 1
CD8+ T cells have an important role in down-modulating
strong Th2 responses. In fact, other studies that used a pulmonary
model in which schistosome eggs are embolized to the lungs of mice
provided evidence that CD8+ T cells can regulate Th2
cell-mediated secondary granulomatous hypersensitivity (9). However,
our data revealed that the liver granulomas of naturally infected
IL-4+/+ and IL-4-/- mice contain about
twofold more CD4+ than CD8+ T cells. Moreover,
about 8% of the CD4+ cells vs 1.5% of the
CD8+ cells were making IFN-. This suggests that the
CD4+, not the CD8+, T cells are the major
source of IFN- within the granuloma. The development of
normal-appearing liver granulomas in ß2m-deficient
animals (10) and in CD8 gene knockout mice (11) also implies that
CD8+ T cells are not critical for granuloma formation, at
least in the early stage of natural infection.
IL-4 can play an important role in helping to differentially polarize
the immune response toward Th2 by opposing IFN- expression (12).
Indeed, in the face of IL-4 deficiency, schistosome granulomas did make
somewhat more IFN-. This was evident from both the flow cytometry
and ELISA data. Yet, in the absence of IL-4, the natural granulomatous
response to schistosome eggs still made little IFN- and failed to
display other features of Th1-type inflammation (1). This suggests that
there are other mechanisms restraining Th1 expression in
schistosomiasis.
The low levels of IFN- emanating from the schistosome granulomas of
IL-4-/- mice could have signified that the lesions
contained few cells capable of IFN- synthesis. As revealed here,
this clearly was not the case. An alternative explanation was that the
inflammation contained cytokine immunoregulatory circuitry independent
of IL-4 that prevented full IFN- production.
Several inflammatory mediators can regulate IFN- expression. Among
these are IL-10, TGF-ß, and IL-12. Our experiments suggest that
ongoing IFN- production in the schistosome granuloma of both
IL-4+/+ and IL-4-/- animals is at least
partly subject to regulation by these molecules. Also, the data show
that the granuloma cells particularly of IL-4-/- mice had
substantial reserve IFN- secretory capacity.
IL-10, TGF-ß, and IL-12 all appeared to act predominantly on the
granuloma Thy1.2+ T cell subset. The NK1.1 cell component
showed little responsiveness. It was particularly surprising that
IL-12, a molecule noteworthy for its strong stimulatory effects on NK
cells, caused few NK cells to produce IFN-. The ratio of granuloma T
cells to NK1.1+ cells expressing IFN- after rIL-12
stimulation was at least 30:1.
There is substantial evidence that IL-10 and TGF-ß have important
immunoregulatory roles in schistosomiasis or other forms of chronic
granulomatous inflammation. Macrophages from schistosome granulomas are
at least one source of IL-10, that can inhibit APC function (13). IL-10
can limit IFN- responses to SEA in the lung, regional lymph nodes,
and spleen (14, 15). Administration of exogenous IL-10 to mice
substantially diminishes schistosome egg-induced granuloma formation in
lung and liver (16). Less well defined is the role of TGF-ß in the
granulomatous response of schistosomiasis (17). TGF-ß is produced
widely and can modulate several aspects of inflammatory responses (18).
It is essential for maintaining normal immune function (19). It is well
appreciated that TGF-ß inhibits IFN- expression. TGF-ß may be
particularly important for controlling IFN- production at mucosal
surfaces and limiting intestinal inflammation (20). Excess TGF-ß
production may increase susceptibility to Leishmania and
mycobacterial infections (21, 22).
As reported here, it was interesting that blockade of either endogenous
IL-10 or TGF-ß activity in dispersed granuloma cell cultures resulted
in near maximal IFN- secretion, whereas simultaneous blockade of
both molecules had no significant additive effect. This implied that
IL-10 and TGF-ß act synergistically within the schistosome
egg-induced inflammation to control IFN- production.
Precisely how schistosome ova prevent Th1 cell activation and rapidly promote Th2 is incompletely understood. IL-10 appears to partly mediate the process. Activation of the innate immune response by molecules other than peptide Ags may be the initial critical factor. A carbohydrate, lacto-N-fucopentaose III in schistosome ova can stimulate B220+ B cells to produce IL-10 and PGE2, which are both molecules that can down-modulate Th1 expression (23). B-1 B cells are particularly responsive (24). Others suggest that selective activation of chemokines is an important factor (25).
There are several major new observations presented in this paper. It
was shown that granulomas have NK1.1+ cells, some of which
bear CD3. Yet, T cells, not NK or NK T cells, produce IFN- within
the granulomas of naturally infected mice. This IFN- production is
subject to IL-10, TGF-ß, and IL-12 regulation at the site of
inflammation. Moreover, the IL-4-/- mice have substantial
reserve IFN--generating capacity, which is restricted by these
cytokine immunoregulatory molecules.
Only uncommitted and Th1 cells express functional receptors for IL-12
(26, 27). There are many IFN--producing T cells responsive to
IL-12 within the liver granulomas of schistosomiasis. This
suggests that these inflammatory lesions, which are strong Th2
responses, actually contain substantial numbers of Th1 or Th0
cells.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joel V. Weinstock, Department of Internal Medicine, 4607 JCP, University of Iowa, Iowa City, IA 52242.
3 Abbreviations used in this paper: SEA, soluble egg antigen; NMS, normal mouse serum; PE, phycoerythrin.
Received for publication July 10, 1997. Accepted for publication January 9, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking. J. Exp. Med. 183:2391.-interferon-deficient mice chronically infected with Schistosoma mansoni. Infect. Immun. 65:2583.[Abstract]
and TGF-ß responses regulate the occurrence of mucosal inflammation. Immunol. Today 18:61.[Medline]
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