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Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA 94301;
Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Laboratory of Parasitic Diseases, Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
§
Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mAb prevented intestinal pathology and
significantly prolonged time to death. Treatment of these animals with
anti-IL-12 mAb also prevented the pathology. Significantly greater
amounts of IFN- mRNA were detected in the lamina propria lymphocytes
obtained from the small intestine of infected IL-10-/-
mice than those from infected control mice. In common with
C57BL/6-background IL-10-/- mice, BALB/c-background
IL-10-/- mice all died developing intestinal pathology
after infection. Control BALB/c mice all survived even after infection
with 100 cysts and did not develop the intestinal lesions. Treatment
with anti-IFN- mAb prevented the pathology and prolonged time to
death of the infected IL-10-/- mice. These results
strongly suggest that IL-10 plays a critical role in down-regulating
IFN- production in the small intestine following sublethal peroral
infection with Toxoplasma gondii and that this
down-regulatory effect of IL-10 is required for prevention of
development of IFN--mediated intestinal pathology and mortality in
both genetically resistant BALB/c and susceptible C57BL/6
mice. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Resistance of mice to mortality following acute peroral infection with T. gondii is under genetic control (7, 8, 9, 10). Multiple genes including one linked to the MHC complex are involved in this control (7, 10). Since the MHC encodes major recognition and immunoregulatory molecules, it is likely that the genes responsible for control of resistance against acute toxoplasmosis, or at least some of them, do so by regulating the immune response to the parasite. Thus, to understand the immunopathogenesis of acute toxoplasmosis, it is important to study the factors underlying the genetic regulation of resistance.
With regard to genetic regulation of resistance against peroral
infection with T. gondii, IFN- has been shown to be
required for survival of resistant strains of mice following infection
(11, 12). In contrast, we recently found that IFN-
contributes to the early mortality of infected, genetically susceptible
C57BL/6 mice (13). Severe necrosis of the small intestine
was observed in association with mortality in infected C57BL/6 mice,
and the pathology was shown to be mediated by IFN-
(13). In this case, local IFN- production in the small
intestine appears to become overly stimulated and the excess IFN-
induces the immunopathology and contributes to early mortality
(13). These results strongly suggest that regulation of
regional IFN- production in the small intestine is critical for
determining whether this cytokine is protective or detrimental in the
immunopathogenesis of acute toxoplasmosis and for determining genetic
resistance/susceptibility of the host to infection.
IL-10 has been shown to play an important role in down-regulating
IFN- production in C57BL/6 mice following i.p. infection with
T. gondii (14, 15). In these studies, infected,
C57BL/6-background IL-10-targeted mutant
(IL-10-/-) mice developed enhanced liver
pathology characterized by increased cellular infiltration and intense
necrosis in association with increased serum levels of IFN- as
compared with control mice (14). However, it is still
unknown whether IL-10 plays an important role in resistance to this
parasite through the natural route of infection and whether this
cytokine is involved in genetic regulation of resistance to the
infection. Therefore, in the present study, we examined the role of
IL-10 in the immunopathogenesis of acute toxoplasmosis following
peroral infection with T. gondii in both genetically
susceptible C57BL/6 and resistant BALB/c mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6- and BALB/c-background IL-10-/-
mice were bred at specific pathogen-free conditions in our animal
facilities, and these animals do not develop colitis until 4–6 mo of
age under these conditions. These animals had been fully backcrossed to
either strains (16). Age- and sex-matched C57BL/6 and
BALB/c mice were obtained from The Jackson Laboratory (Bar Harbor, ME).
Female and male mice were 8–10 wk old when used. Females were used in
most studies. There were three to five mice in each experimental group
to study histological changes and five to seven mice in each
experimental group to study mortality; four mice were used in each
experimental group for detection of mRNA for IFN-. Each experiment
was performed at least twice.
Infection with T. gondii
Cysts of the ME49 strain were obtained from brains of Swiss-Webster mice (Bantin and Kingman, Fremont, CA) that had been infected i.p. with 10 cysts for 2–3 mo as described previously (17). For peroral infection, C57BL/6-background IL-10-/- and control mice were infected with 20 cysts by gavage. BALB/c-background IL-10-/- and control mice were infected with either 20 or 100 cysts in the same manner.
Histopathology
Groups of three to five mice were euthanized by asphyxiation with CO2 at 9 days after peroral infection with the ME49 strain. Their brains, lungs, hearts, livers, spleens, and small and large intestines were removed and immediately fixed in a solution containing 10% Formalin, 70% ethanol, and 5% acetic acid. Two to four 5-µm-thick sections (50 or 100 µm distance between sections) of each organ from each mouse were stained with hematoxylin and eosin and by the immunoperoxidase method with rabbit anti-T. gondii IgG Ab (18). Sections stained with hematoxylin and eosin were evaluated for inflammatory changes and sections stained by the immunoperoxidase method were evaluated for the number of parasitophorous vacuoles containing T. gondii tachyzoites. Histological changes were consistent between individual mice in the same group and between sections from the same organ of each mouse. Each slide was evaluated by two investigators. The results of each investigator were essentially the same.
Small intestines were cut into two pieces and each rolled on itself to make a "Swiss roll." The entire length of the small intestines were examined histologically. The length of ileum with necrosis of villi was measured by a scale after microscopic evaluation. Numbers of parasitophorous vacuoles that contained tachyzoites in the ileum were counted under x400 magnification.
Depletion of CD4+ T cells in vivo
Mice were injected i.p. with 1 mg of anti-CD4 mAb (GK1.5) (19) daily for 3 days beginning 3 days before infection and thereafter every other day. Control mice were injected 1 mg of control IgG (GL113; rat anti-Escherichia coli ß-galactosidase mAb) in the same manner.
Treatment with mAbs against IFN- and IL-12
Mice were injected i.p. with 2 mg of rat anti-mouse IFN-
mAb (XMG1.2) (20) once daily for 5 days beginning 5 or 6
days after infection. Control mice were injected with 2 mg of control
IgG in the same manner (GL113). In another experiments, mice were
injected i.p. with 1 mg of rat anti-mouse IL-12 mAb (C17.8.20) at
2 h before and 7 days after infection (21). Control
mice were injected with 1 mg of normal rat IgG (Sigma, St. Louis, MO)
in the same manner.
Isolation of intraepithelial lymphocytes (IEL)5 and lamina propria lymphocytes (LPL)
At 7 days after infection, IEL and LPL were obtained from mice as described previously (22, 23, 24) with some modifications (25). Briefly, the entire length of the small intestine was removed from each mouse and flushed with saline to eliminate its contents. After Peyer’s patches were excised, the intestines were opened longitudinally, washed extensively in saline, and chopped into pieces of 0.5–1 cm length. Thereafter, the pieces of the small intestines from two mice were pooled and incubated in Dulbecco’s PBS (pH 7.3; Life Technologies, Gaithersburg, MD) containing 2 mM EDTA (Sigma) at 37°C for 15 min on a rotator. The supernatant which contains IEL was collected. The remaining tissue fragments were incubated again in Dulbecco’s PBS containing 2 mM EDTA and the supernatant was collected as described above. The supernatant containing IEL was applied to a glass-wool column to isolate IEL. The remaining tissue fragments were incubated in 0.015% collagenase (Wako Pure Chemicals, Osaka, Japan) in MEM (Sigma) for 30 min and pressed through 200-gauge steel mesh. LPL preparations were washed in MEM and resuspended in 100% Percoll (Pharmacia LKB, Uppsala, Sweden). This cell suspension was underlayered with 40% Percoll and thereafter centrifuged at 850 x g for 20 min. LPL were collected from the interface and washed in MEM before use. The viabilities of the lymphocyte preparations were examined by trypan blue dye exclusion. Their viabilities were 90–96% in IEL and 70–86% in LPL.
Detection of mRNA for IFN- in IEL and LPL
RNA was isolated from IEL and LPL using the RNA-STAT RNA
extraction kit (Tel-Test B, Friendswood, TX) following the
manufacturer’s protocol. The OD at 260 nm was used to estimate the
concentration of total RNA. cDNA was synthesized using the RNA as
described previously (26, 27). PCR for IFN- and
ß-actin was performed with 2.5 µl of the original cDNA reaction
mixture with a GeneAmp 9600 thermocycler (Perkin-Elmer, Emeryville, CA)
as described previously (26, 27). Specific primers for
IFN- and ß-actin (Clontech, Palo Alto, CA) designed to span at
least one intron allowed differentiation of amplified target DNA
derived either from cDNA or genomic DNA in the PCR.
Detection of PCR products
Ten microliters of the final reaction mixture of PCR was
electrophoresed at 100 V for 1 h on a 1.2% agarose gel and
denatured (26, 27). The DNA was then transferred to a
Duralon-UV-membrane (Stratagene, La Jolla, CA) by standard blotting
procedure (28) and UV cross-linked. Oligonucleotide probes
for ß-actin and IFN- (Clontech) that hybridize to the PCR products
wholly within the region amplified by the primers were end labeled as
described in the 3'-oligolabeling and signal amplification system for
the FluorImager (Amersham, Little Chalfont, U.K.). Hybridization was
detected by scanning the membranes using a FluorImager Storm 860
(Molecular Dynamics, Sunnyvale, CA) as previously described
(27). Quantification of mRNA was performed by densitometry
analysis with the FluorImager and normalized to the ß-actin
level.
Flow cytometry
One x 106 IEL and LPL were
pretreated on ice for 10 min with 10 µl of a predetermined optimal
concentration of anti-FcII/III receptors (2.4G2) to block
non-Ag-specific binding of Abs to the FcII/III receptors.
Thereafter, the cells were incubated on ice for 30 min with 10 µl of
optimal concentrations of PE-conjugated anti-CD4 mAb (RM4-5) and
FITC-conjugated anti-CD8 mAb (7). The mAbs were
obtained from Phar- Mingen (San Diego, CA). Analysis of stained
cells was performed with a FACScan (Becton Dickinson, Mountain View,
CA). Dead cells were gated out on the basis of propidium iodide
staining.
Statistical analysis
Levels of significance for amounts of mRNA for IFN- in LPL
and IEL, length of ileum with necrosis, numbers of parasitophorous
vacuoles containing tachyzoites in the ilea, and time to death of mice
were determined using Student’s t, alternate Welch
t, or Wilcoxon rank sum test. Alternative Welch t
test was applied when SDs were significantly different between groups
tested. Wilcoxon rank sum test was applied when SD of a group tested
was zero. Levels of significance for mortality in mice were determined
using Fisher’s exact test. A p < 0.05 was considered
to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-10-/- and control mice were infected
perorally with 20 cysts of the ME49 strain.
IL-10-/- mice all (12/12) died from 8 to 13
days after infection, whereas only 20% (2/10) of control mice died
(p = 0.0001, Fig. 1
). IL-10-/- mice
appeared to be healthy until 6 days after infection; thereafter, they
quickly developed piloerection, huddled, and lost mobility.
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Because of the remarkable difference in mortality between
IL-10-/- and control mice, we examined their
brains, hearts, lungs, spleens, livers, small intestines, and large
intestines at 9 days after infection to determine whether histological
changes differ between infected IL-10-/- and
control mice. The most pronounced histological differences between
these strains of mice were observed in the small intestine. Severe
necrosis of the villi and mucosal cells was observed in large areas of
the small intestine, mostly in the ileum, in
IL-10-/- mice (Figs. 2 and
3D). In contrast, such
histological changes were not observed in either normal or infected
control mice or normal IL-10-/- mice (Figs. 2 and 3, A–C). There was a tendency for
IL-10-/- mice to show greater numbers of
tachyzoites than did control mice; however, the difference did not
reach statistical significance (the numbers of parasitophorous
vacuoles/cm of ileum = 96.3 ± 104 for
IL-10-/- vs 34.7 ± 26.8 for control
animals; p = 0.058). The small intestine was the only
organ in which large numbers of tachyzoites were detected in either
strain of mice. Necrosis was also observed in the large intestine of
infected IL-10-/- mice, although only a few
tachyzoites were detected in this organ. Inflammatory changes were also
observed in livers and lungs of IL-10-/- mice.
These consisted of necrosis of hepatocytes as well as pulmonary
infiltration of mononuclear cells. Nevertheless, the same changes were
also observed although less frequently in infected control mice (data
not shown).
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Since the necrosis in the small intestine of
IL-10-/- mice sublethally infected with 20
cysts observed in the present study was similar to that which we
previously described in control mice following lethal infection with
100 cysts (13), we performed studies to examine whether
the same mechanism underlies the pathologic response observed in both
situations. First, we examined whether necrosis in the small intestine
in IL-10-/- mice is dependent on
CD4+ T cells. IL-10-/-
mice were treated with anti-CD4 mAb to deplete
CD4+ T cells and histological studies were
performed on their small intestines at 9 days after infection. We
previously reported that anti-CD4 mAb treatment effectively
depleted gut-associated CD4+ T cells
(13). Whereas mice treated with control IgG developed
severe necrosis of the villi in large areas of their small intestines,
those treated with anti-CD4 mAb lacked these histological changes
(p = 0.014, Fig. 4).
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). The above results
indicate that necrosis in the small intestine in infected
IL-10-/- mice is induced by
CD4+ T cells and that CD4+
T cells predispose to early death in these animals.
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or anti-IL-12 mAbs on
development of necrosis in the small intestine and time to death in
infected C57BL/6-background IL-10-/- mice
We next examined whether CD4+ T
cell-dependent development of necrosis in the small intestine in
infected IL-10-/- mice is mediated by IFN-.
IL-10-/- mice were injected with 2 mg of
anti-IFN- mAb to neutralize activity of endogenous IFN- daily
beginning at 6 days and the animals were necropsied for histopathologic
examination at 9 days after infection. Severe necrosis was observed in
large areas of the ileum of mice treated with control IgG but not in
mice treated with anti-IFN- mAb (p =
0.014, Fig. 6). To examine whether IL-12
plays an important role in induction of the IFN--mediated
immunopathology, IL-10-/- mice were treated
with anti-IL-12 mAb at 2 h before and 7 days after infection.
Mice treated with anti-IL-12 did not develop intestinal pathology
(p = 0.014, Fig. 6). In contrast, mice treated
with anti-IL-12 mAb at 3 days after infection developed the
pathology (data not shown). These results indicate that IL-12 plays a
critical role in the induction of IFN--mediated necrosis in the
small intestine in IL-10-/- mice during the
early stage of infection with T. gondii.
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mAb to examine its effect on mortality. For this
purpose, mice were treated with anti-IFN- mAb daily for 5 days
beginning 6 days after infection. Mice treated with anti-IFN-
mAb survived significantly longer than mice treated with control IgG
(p = 0.0002, Fig. 7). These results indicate that IFN-
mediates development of necrosis in the small intestine in
IL-10-/- mice following peroral infection with
T. gondii and that this cytokine contributes to early death
of the same animals.
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in IEL and LPL of the small intestine in
infected C57BL/6-background IL-10-/- and control mice
Since necrosis in the small intestine occurred in
IL-10-/- mice but not in control C57BL/6
animals following peroral infection with 20 cysts of the ME49 strain
and since the necrosis was found to be mediated by IFN-, we examined
whether IFN- expression is accelerated in the small intestine of
infected IL-10-/- mice. For this purpose, IEL
and LPL were obtained from the small intestines of
IL-10-/- and control mice at 7 days after
infection. Significantly greater IFN-:ß-actin mRNA ratios were
detected in LPL obtained from infected IL-10-/-
mice than that from infected control animals (p
= 0.003, Fig. 8), whereas
IFN-:ß-actin mRNA ratios did not differ in IEL from these mice
(p = 0.122, Fig. 8). Large amounts of IL-10
mRNA were detected in both IEL and LPL of the control animals (data not
shown). Both IEL and LPL obtained from the
IL-10-/- animals had significantly higher
relative percentages of CD4+ T cells than those
from the control animals (16.2 ± 6.1% vs 6.1 ± 0.8% for
IEL (p = 0.012); 28.2 ± 1.2% vs
22.0 ± 3.2% for LPL (p = 0.011)). Total
numbers of IEL and LPL did not differ between these mice.
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Based on the evidence that IL-10 is required for prevention of
mortality and intestinal necrosis in genetically susceptible C57BL/6
mice following a sublethal low-dose infection, we examined whether
IL-10 is required for genetic resistance of BALB/c mice against
infection. BALB/c-background IL-10-/- and
control mice were infected perorally with 100 cysts of the ME49 strain.
This is a dose in which genetically resistant BALB/c mice survive but
susceptible C57BL/6 mice die during the acute stage (9, 13). BALB/c-background IL-10-/- animals
all died from 9 to 11 days after infection whereas control animals all
survived (Fig. 9A). To examine
whether the IL-10-/- mice are able to survive
when infected with fewer cysts, they were infected perorally with 20
cysts. The IL-10-/- animals again all died from
9 to 11 days after infection (Fig. 9B). Control mice all
survived (Fig. 9B). Of interest, the BALB/c-background
IL-10-/- mice died at the same time as did
C57BL/6-background IL-10-/- mice infected in
parallel with the BALB/c-background mice (Fig. 9B). These
results indicate that genetic resistance of BALB/c mice against
mortality following peroral infection with T. gondii
requires IL-10.
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Effect of treatment with anti-IFN- mAb on development of
necrosis in the small intestine and time to death in infected
BALB/c-background IL-10-/- mice
To examine whether IFN- contributes to the intestinal pathology
and mortality in BALB/c-background IL-10-/-
mice following infection, the IL-10-/- animals
were injected with 2 mg of anti-IFN- mAb daily beginning 5 days
after infection with 100 cysts. Animals treated with anti-IFN-
mAb survived significantly longer than those treated with control IgG
(p < 0.001, Fig. 10). Histological studies were
performed on their small intestines at 9 days after infection. Numbers
of areas of focal necrotic regions were significantly less in the
animals treated with anti-IFN- mAb than those treated with
control IgG (p = 0.021, Fig. 11). These results indicate that
IFN- plays a critical role in development of the intestinal
pathology and mortality in BALB/c-background
IL-10-/- mice following peroral infection with
T. gondii.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast to remarkable differences in mortality and intestinal
pathology between infected IL-10-/- and control
mice, there were no differences in the numbers of tachyzoites detected
in the small intestines in these animals. This evidence argues that
IL-10 is not directly controlling parasite growth but regulating the
immune response induced. This possibility is supported by the evidence
that neutralization of IFN- by treatment with anti-IFN- mAb
inhibited intestinal pathology and prolonged time to death in both
BALB/c- and C57BL/6-background IL-10-/- mice
following infection. Thus, IFN- mediates the pathology and
contributes to mortality in both strains of
IL-10-/- mice. Since the intestinal lesions
were the most severe histological changes in these animals, the
IFN--mediated pathology appears to contribute to their mortality.
Studies using RT-PCR revealed significantly greater IFN-:ß-actin
mRNA ratios in LPL obtained from the small intestine of infected
C57BL/6-background IL-10-/- than control mice,
strongly suggesting that IL-10 plays a crucial role in down-regulation
of IFN- production by the LPL and in prevention of IFN--mediated
pathology in the intestine following peroral infection with T.
gondii. This is further supported by our finding of enhanced
expression of IL-10 mRNA by LPL of infected control mice. Of interest,
the IFN-:ß-actin mRNA ratios did not differ in IEL from the small
intestine of infected IL-10-/- and control
mice. Thus, the role of IL-10 in down-regulation of IFN- production
may differ between IEL and LPL following infection or it may act at
different time points in the LPL. Since the numbers of LPL obtained
from the small intestines of infected IL-10-/-
mice were similar to those of IEL (6–8 x
106 cells/mouse on average), and since
IFN-:ß-actin mRNA ratios were significantly up-regulated in LPL as
mentioned above, overproduction of IFN- by LPL appears to contribute
to their intestinal pathology although the cytokine produced by IEL may
also partially participate in the pathology.
IFN- has been shown to be critical for prevention of tachyzoite
proliferation and mortality in animals infected with T.
gondii (11, 12, 21). Our observation of the
importance of down-regulation of IFN- production by IL-10 indicates
that both the induction of IFN- and its regulation by IL-10 are key
elements in host resistance to this parasite.
Depletion of CD4+ T cells by treatment with
anti-CD4 mAb was shown to prevent intestinal necrosis and early
mortality in infected IL-10-/- mice. Since
IFN-, most likely produced by LPL, was demonstrated to mediate the
pathology and mortality in the infected
IL-10-/- animals in the present study and since
the relative percentages of CD4+ T cells
increased in their intestinal lymphocyte populations, IFN-
production by CD4+ T cells in LPL appears to be
an important factor which contributes to both pathologic sequelae.
CD4+ T cells may also play an indirect role by
stimulating CD8+ T cells to produce IFN-.
However, CD8+ T cells do not seem to play a major
role in the intestinal pathology since depletion of
CD8+ T cells did not prevent the pathology in our
previous study using lethally infected C57BL/6 mice (13).
Furthermore, the present study demonstrates that the development of
intestinal pathology in infected IL-10-/- mice
is IL-12 dependent. Since IL-12 is a potent inducer of Th1-type
cytokine production by CD4+ T cells
(29, 30, 31), IL-12-mediated IFN- production by intestinal
CD4+ T cells is likely to be a critical
determinant of the marked susceptibility of
IL-10-/- mice to peroral infection with
T. gondii. NK cells may also contribute partially to their
pathology and mortality since it has been reported that T.
gondii infection induces IL-12-dependent IFN- production by NK
cells (32, 33).
Buzoni-Gatel et al. (34) have recently reported that
CD8+ IEL produce IFN- and play a protective
role against peroral infection with T. gondii. Our findings
suggest that in the case of the small intestine,
CD4+ T cells in LPL are likely the major source
of the IFN- production responsible for disease induction in T.
gondii-infected IL-10-/- mice. Whether the
same CD4+ LPL population plays a role in
IFN--dependent control of parasite growth in the intestine in the
presence of IL-10 remains to be established.
IL-10-/- mice have been shown to spontaneously
develop chronic enterocolitis (35). This colitis is
mediated by IFN- produced by CD4+ Th1-type T
cells of LPL (16, 36, 37). Normal intestinal microflora is
suggested to play a causal role in induction of the detrimental
Th1-type immune response in the colon of the animals (35).
The present study suggests that IFN- production by
CD4+ T cells of LPL induces necrosis in the small
intestine in T. gondii-infected
IL-10-/- mice. Thus, CD4+
T cells appear to be the major source of this cytokine in LPL during
the pathogenic response to two highly distinct microorganisms.
Control C57BL/6 mice die during the acute stage of infection when
infected with a high dose (100) of T. gondii cysts because
of their genetic susceptibility (9, 13). We previously
reported that CD4+ T cell-dependent
IFN--mediated necrosis in the small intestine occurs in these mice
following lethal infection (13). This is in contrast to
the consequences of sublethal infection described in the present study
in which control C57BL/6 mice were able to prevent pathology through a
down-regulatory effect of IL-10 on IFN- production. Thus, it appears
that the role of IL-10 in the pathogenesis of acute toxoplasmosis
differs depending on the dose of infection in genetically susceptible
C57BL/6 mice. It may be that lethal infection causes a suppression of
IL-10 production in the susceptible animals, resulting in the same
pathologic consequences observed in IL-10-/-
mice. Alternatively, the lethal (high) dose infection may induce a
particularly strong and early IFN- response that cannot be
down-regulated by the ensuing IL-10 response.
When necrosis of the small intestine occurred in infected
IL-10-/- mice, large numbers of tachyzoites
were detected only in that organ. In previous studies using i.p.
infection, necrosis in the liver was noted as a major pathologic
correlate of mortality in these mice (14). In recent work,
we have observed large numbers of the parasite in the liver but not in
the intestine following i.p. infection (our unpublished data). This
evidence strongly argues that the regulation of IFN--mediated
regional immune responses in the target organ(s) where large numbers of
tachyzoites proliferate is critical for determining susceptibility to
infection. The organs involved appear to differ depending on the route
and the stage of infection.
The data from the present study strongly suggest a crucial role of
IL-10 in preventing the IFN--mediated protective immune response
from becoming pathogenic during the acute stage of T. gondii
infection initiated by the peroral route. Thus, resistance against
T. gondii requires the development of a finely tuned balance
between the host protective and host detrimental effects of the
regional Th1-immune response. It is of interest that there were no
differences in time to death between BALB/c- and C57BL/6-background
IL-10-/- mice following infection, although
control BALB/c and C57BL/6 mice markedly differ in their susceptibility
to development of intestinal pathology (13) and mortality
(9, 13) after infection. Thus, IL-10 is an essential
determinant of host resistance to T. gondii, and in its
absence the genetic regulation of this process is overridden.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yasuhiro Suzuki, Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, 860 Bryant Street, Palo Alto, CA 94301.
3 Current address: Bayer Corporation, 800 Dwight Way, Berkeley, CA 94710.
4 Current address: Institut für Infektionsmedizin, Abteilung für Medizinsche Mikrobiologie, Universitätsklinikum Benjamin Franklin der Freien Universität Berlin, 12203 Berlin, Germany.
5 Abbreviations used in this paper: IEL, intraepithelial lymphocyte; LPL, lamina propria lymphocyte.
Received for publication August 13, 1999. Accepted for publication March 8, 2000.
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  K. K. McKinstry, T. M. Strutt, A. Buck, J. D. Curtis, J. P. Dibble, G. Huston, M. Tighe, H. Hamada, S. Sell, R. W. Dutton, et al. IL-10 Deficiency Unleashes an Influenza-Specific Th17 Response and Enhances Survival against High-Dose Challenge J. Immunol., June 15, 2009; 182(12): 7353 - 7363. [Abstract] [Full Text] [PDF]
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K. N. Couper, P. A. Lanthier, G. Perona-Wright, L. W. Kummer, W. Chen, S. T. Smiley, M. Mohrs, and L. L. Johnson Anti-CD25 Antibody-Mediated Depletion of Effector T Cell Populations Enhances Susceptibility of Mice to Acute but Not Chronic Toxoplasma gondii Infection J. Immunol., April 1, 2009; 182(7): 3985 - 3994. [Abstract] [Full Text] [PDF]
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 C. W. Lee, W. Sukhumavasi, and E. Y. Denkers Phosphoinositide-3-Kinase-Dependent, MyD88-Independent Induction of CC-Type Chemokines Characterizes the Macrophage Response to Toxoplasma gondii Strains with High Virulence Infect. Immun., December 1, 2007; 75(12): 5788 - 5797. [Abstract] [Full Text] [PDF]
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 M. Roselli, A. Finamore, M. S. Britti, S. R. Konstantinov, H. Smidt, W. M. de Vos, and E. Mengheri The Novel Porcine Lactobacillus sobrius Strain Protects Intestinal Cells from Enterotoxigenic Escherichia coli K88 Infection and Prevents Membrane Barrier Damage J. Nutr., December 1, 2007; 137(12): 2709 - 2716. [Abstract] [Full Text] [PDF]
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 D. Jankovic, M. C. Kullberg, C. G. Feng, R. S. Goldszmid, C. M. Collazo, M. Wilson, T. A. Wynn, M. Kamanaka, R. A. Flavell, and A. Sher Conventional T-bet+Foxp3- Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection J. Exp. Med., February 19, 2007; 204(2): 273 - 283. [Abstract] [Full Text] [PDF]
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S. Bennouna, W. Sukhumavasi, and E. Y. Denkers Toxoplasma gondii Inhibits Toll-Like Receptor 4 Ligand-Induced Mobilization of Intracellular Tumor Necrosis Factor Alpha to the Surface of Mouse Peritoneal Neutrophils Infect. Immun., July 1, 2006; 74(7): 4274 - 4281. [Abstract] [Full Text] [PDF]
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C. E. Egan, J. E. Dalton, E. M. Andrew, J. E. Smith, M.-J. Gubbels, B. Striepen, and S. R. Carding A Requirement for the V{gamma}1+ Subset of Peripheral {gamma}{delta} T Cells in the Control of the Systemic Growth of Toxoplasma gondii and Infection-Induced Pathology J. Immunol., December 15, 2005; 175(12): 8191 - 8199. [Abstract] [Full Text] [PDF]
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C. Ronet, S. Darche, M. L. de Moraes, S. Miyake, T. Yamamura, J. A. Louis, L. H. Kasper, and D. Buzoni-Gatel NKT Cells Are Critical for the Initiation of an Inflammatory Bowel Response against Toxoplasma gondii J. Immunol., July 15, 2005; 175(2): 899 - 908. [Abstract] [Full Text] [PDF]
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S. T. Smiley, P. A. Lanthier, K. N. Couper, F. M. Szaba, J. E. Boyson, W. Chen, and L. L. Johnson Exacerbated Susceptibility to Infection-Stimulated Immunopathology in CD1d-Deficient Mice J. Immunol., June 15, 2005; 174(12): 7904 - 7911. [Abstract] [Full Text] [PDF]
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H. D. Dawson, E. Beshah, S. Nishi, G. Solano-Aguilar, M. Morimoto, A. Zhao, K. B. Madden, T. K. Ledbetter, J. P. Dubey, T. Shea-Donohue, et al. Localized Multigene Expression Patterns Support an Evolving Th1/Th2-Like Paradigm in Response to Infections with Toxoplasma gondii and Ascaris suum Infect. Immun., February 1, 2005; 73(2): 1116 - 1128. [Abstract] [Full Text] [PDF]
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M. N. Kelly, J. K. Kolls, K. Happel, J. D. Schwartzman, P. Schwarzenberger, C. Combe, M. Moretto, and I. A. Khan Interleukin-17/Interleukin-17 Receptor-Mediated Signaling Is Important for Generation of an Optimal Polymorphonuclear Response against Toxoplasma gondii Infection Infect. Immun., January 1, 2005; 73(1): 617 - 621. [Abstract] [Full Text] [PDF]
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F. Lu, S. Huang, and L. H. Kasper CD4+ T Cells in the Pathogenesis of Murine Ocular Toxoplasmosis Infect. Immun., September 1, 2004; 72(9): 4966 - 4972. [Abstract] [Full Text] [PDF]
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N. Rachinel, D. Buzoni-Gatel, C. Dutta, F. J. D. Mennechet, S. Luangsay, L. A. Minns, M. E. Grigg, S. Tomavo, J. C. Boothroyd, and L. H. Kasper The Induction of Acute Ileitis by a Single Microbial Antigen of Toxoplasma gondii J. Immunol., August 15, 2004; 173(4): 2725 - 2735. [Abstract] [Full Text] [PDF]
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 M. Chen, F. Aosai, K. Norose, H.-S. Mun, H. Ishikura, S. Hirose, L.-X. Piao, H. Fang, and A. Yano Toxoplasma gondii infection inhibits the development of lupus-like syndrome in autoimmune (New Zealand Black x New Zealand White) F1 mice Int. Immunol., July 1, 2004; 16(7): 937 - 946. [Abstract] [Full Text] [PDF]
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S. Duleu, P. Vincendeau, P. Courtois, S. Semballa, I. Lagroye, S. Daulouede, J.-L. Boucher, K. T. Wilson, B. Veyret, and A. P. Gobert Mouse Strain Susceptibility to Trypanosome Infection: An Arginase-Dependent Effect J. Immunol., May 15, 2004; 172(10): 6298 - 6303. [Abstract] [Full Text] [PDF]
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L. C. Gavrilescu, B. A. Butcher, L. Del Rio, G. A. Taylor, and E. Y. Denkers STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection Infect. Immun., March 1, 2004; 72(3): 1257 - 1264. [Abstract] [Full Text] [PDF]
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F. Lu, S. Huang, and L. H. Kasper Interleukin-10 and Pathogenesis of Murine Ocular Toxoplasmosis Infect. Immun., December 1, 2003; 71(12): 7159 - 7163. [Abstract] [Full Text] [PDF]
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S. Bennouna, S. K. Bliss, T. J. Curiel, and E. Y. Denkers Cross-Talk in the Innate Immune System: Neutrophils Instruct Recruitment and Activation of Dendritic Cells during Microbial Infection J. Immunol., December 1, 2003; 171(11): 6052 - 6058. [Abstract] [Full Text] [PDF]
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 T. D. Nguyen, G. Bigaignon, D. Markine-Goriaynoff, H. Heremans, T. N. Nguyen, G. Warnier, M. Delmee, M. Warny, S. F. Wolf, C. Uyttenhove, et al. Virulent Toxoplasma gondii strain RH promotes T-cell-independent overproduction of proinflammatory cytokines IL12 and {gamma}-interferon J. Med. Microbiol., October 1, 2003; 52(10): 869 - 876. [Abstract] [Full Text] [PDF]
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M. Chen, F. Aosai, K. Norose, H.-S. Mun, and A. Yano The role of anti-HSP70 autoantibody-forming VH1-JH1 B-1 cells in Toxoplasma gondii-infected mice Int. Immunol., January 1, 2003; 15(1): 39 - 47. [Abstract] [Full Text] [PDF]
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J. Aliberti, C. Serhan, and A. Sher Parasite-induced Lipoxin A4 Is an Endogenous Regulator of IL-12 Production and Immunopathology in Toxoplasma gondii Infection J. Exp. Med., November 4, 2002; 196(9): 1253 - 1262. [Abstract] [Full Text] [PDF]
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S. Wei, F. Marches, J. Borvak, W. Zou, J. Channon, M. White, J. Radke, M.-F. Cesbron-Delauw, and T. J. Curiel Toxoplasma gondii-Infected Human Myeloid Dendritic Cells Induce T-Lymphocyte Dysfunction and Contact-Dependent Apoptosis Infect. Immun., April 1, 2002; 70(4): 1750 - 1760. [Abstract] [Full Text] [PDF]
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D. E. Jones, M. R. Ackermann, U. Wille, C. A. Hunter, and P. Scott Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection Infect. Immun., April 1, 2002; 70(4): 2151 - 2158. [Abstract] [Full Text] [PDF]
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F. J. D. Mennechet, L. H. Kasper, N. Rachinel, W. Li, A. Vandewalle, and D. Buzoni-Gatel Lamina Propria CD4+ T Lymphocytes Synergize with Murine Intestinal Epithelial Cells to Enhance Proinflammatory Response Against an Intracellular Pathogen J. Immunol., March 15, 2002; 168(6): 2988 - 2996. [Abstract] [Full Text] [PDF]
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L. Del Rio, S. Bennouna, J. Salinas, and E. Y. Denkers CXCR2 Deficiency Confers Impaired Neutrophil Recruitment and Increased Susceptibility During Toxoplasma gondii Infection J. Immunol., December 1, 2001; 167(11): 6503 - 6509. [Abstract] [Full Text] [PDF]
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L. C. Gavrilescu and E. Y. Denkers IFN-{{gamma}} Overproduction and High Level Apoptosis Are Associated with High but Not Low Virulence Toxoplasma gondii Infection J. Immunol., July 15, 2001; 167(2): 902 - 909. [Abstract] [Full Text] [PDF]
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L. H. Kasper and D. Buzoni-Gatel Ups and Downs of Mucosal Cellular Immunity against Protozoan Parasites Infect. Immun., January 1, 2001; 69(1): 1 - 8. [Full Text] [PDF]
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