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-Galactosylceramide Before Trypanosoma cruzi Infection Provides Protection or Induces Failure to Thrive1
Infectious Disease Research Institute, Seattle, WA 98104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14 NK T (iNKT) cells are a regulatory subset of
T cells that can contribute to protection against pathogens and to
control of chronic inflammatory diseases. -Galactosylceramide
(-GalCer) is an iNKT cell-specific glycolipid Ag: a single
immunization with -GalCer stimulates robust IFN-
and IL-4
production by iNKT cells, while multiple immunizations stimulate IL-4
production, but limited IFN- production. We recently demonstrated
that iNKT cells help control T. cruzi infection and
affect the chronic Ab response. Therefore, -GalCer treatment might
be used to increase protection or decrease chronic inflammation during
T. cruzi infection. In this report, we show that a
single dose of -GalCer before T. cruzi infection
decreases parasitemia. This protection is independent of IL-12, but
dependent upon iNKT cell IFN-. In addition, -GalCer treatment of
the IFN--/- mice exacerbates parasitemia through IL-4
production. Furthermore, a multiple dose regimen of -GalCer before
T. cruzi infection does not lower parasitemia and,
surprisingly, after parasitemia has resolved, causes poor weight gain.
These data demonstrate that during T. cruzi infection
glycolipids can be used to manipulate iNKT cell responses and suggest
the possibility of developing glycolipid treatments that can increase
protection and possibly decrease the chronic inflammatory
pathology. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We recently reported that during T. cruzi infection V14
TCR invariant NKT
(iNKT)3 cells provide
protection (5). NKT cells are a subset of immune effector
cells distinct from conventional T cells and NK cells in that they
express some receptors typical of both cell types, e.g., the TCR and
the NK1.1 Ag (6, 7). The majority of NKT cells use an
invariant TCR -chain (V14-J281 in mice and V24-JQ in
humans) paired with a limited set of TCR 
-chains (mostly V8.2 in
mice and V11 in humans) (7, 8). In contrast with
conventional T cells, iNKT cells can be stimulated by glycolipids
presented by the MHCI-like CD1d molecular complex to their TCRs
(7, 8). In addition, NKT cell responses can be stimulated
by IL-12 (9). The marine sponge-derived glycolipid
-galactosylceramide (-GalCer) and its analogs are currently the
only known CD1d-restricted iNKT cell TCR ligands
(10, 11, 12).
NKT cells have been shown to provide protection against some infections
(5, 13, 14, 15). Interestingly, NKT cell deficiencies or the
skewing of NKT cells to a Th1 phenotype are associated with several
autoimmune diseases (7, 16, 17, 18). These data suggested that
iNKT cell glycolipid Ag treatments could be used to modulate protective
and pathologic immune responses. Indeed, a single dose of -GalCer
rapidly stimulates iNKT cells to produce IFN- and IL-4 and protects
mice (decreased pathogen burden) from subsequent experimental infection
with Cryptococcus neoformans (19) or
Plasmodium species (20). In contrast, multiple
administrations of -GalCer augment Th2 responses (21)
and protect nonobese diabetic mice against diabetes, a disease mediated
by Th1 responses (22, 23). Furthermore, OCH, an
analog of -GalCer, preferentially stimulates iNKT cell IL-4
secretion and treatment with it prevents severe experimental autoimmune
encephalomyelitis (12). Thus, iNKT cells can be
manipulated with glycolipid Ags to afford protection against
infections and chronic inflammatory autoimmune responses. Since during
T. cruzi infection iNKT cells are stimulated and contribute
to the protective and chronic immune responses, we were interested in
determining whether these iNKT cell responses could be modulated with
the glycolipid Ag, -GalCer (5).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to 10-wk-old wild-type C57BL/6 and wild-type BALB/c mice
were obtained from Bantin and Kingman (Fremont, CA). C57BL/6
J281-/- and BALB/c
J281-/- mice were crossed a minimum of nine
times to either wild-type C57BL/6 or BALB/c mice and bred in the animal
facilities at the University of Washington (24). C57BL/6
IFN--/- and C57BL/6 IL-12
p40-/- mice were purchased from The Jackson
Laboratory (Bar Harbor, ME).
-GalCer administration
Mice were injected i.p. with -GalCer (supplied by Dr. Y.
Koezuka, Kirin Brewery, Gunma, Japan) either once 24 h before or
three times (on days 7, 4, and 1) before T. cruzi infection.
-GalCer was diluted in DMEM (BioWhittaker, Walkersville, MD)
immediately before administration.
T. cruzi infection of mice and parasitemia determination
A recently derived clone of the CL strain subclone 3 was used (25, 26). Trypomastigotes were obtained from culture supernatants of infected 3T3 cells grown in DMEM (BioWhittaker) supplemented with 10% heat-inactivated calf serum (BioWhittaker) and 50,000 U penicillin/streptomycin (BioWhittaker). Mice were infected by i.p. injection of trypomastigotes.
Parasitemia was monitored by venesection of the tail. Two microliters of blood was diluted in 1.66% ammonium chloride in PBS, and the trypomastigotes were counted on a hemocytometer by an investigator unaware of the sample status (27).
Anti-IL-4 Ab treatment
Anti-IL-4 Ab was purified from the supernatant of 11B11 cells
(American Type Culture Collection, Manassas, VA) using protein G (Life
Technologies, Gaithersburg, MD). Mice were injected i.p. with 1.5 mg Ab
1 h before -GalCer treatment.
Analysis of Ab responses
Individual blood samples from T. cruzi-infected mice were collected by venesection of the tail, allowed to clot during overnight incubation at 4°C, and sera were prepared and stored at -20°C. Individual sera were analyzed using Ab capture ELISAs. ELISA plates were coated with 5 µg/ml SA85-1.1 recombinant protein. The preparation of SA85-1.1 recombinant protein and serum Ab detection by ELISA have been described previously (5, 28).
Statistics
The p values for parasitemia were determined using Student’s t test (Microsoft Excel; Microsoft, Redmond, WA). The p values for survival were determined using the log rank statistic of Kaplan-Meier survival analysis (SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-GalCer
treatment decreases parasitemia
Our recent studies demonstrate that during T. cruzi
infection, iNKT cells are stimulated and provide protection
(5). -GalCer treatment before experimental infection
with Plasmodium yoelli or Cryptococcus
neoformans is protective (19, 20). To examine whether
-GalCer treatment before T. cruzi infection could augment
the protective iNKT cell response, C57BL/6 mice were treated with
-GalCer 1 day before infection with a sublethal inoculum of
trypomastigotes. Parasitemia was significantly reduced in the
-GalCer-treated group compared with the diluent-treated group (Fig. 1
a, p <
0.01). We then determined whether C57BL/6 mice could be protected from
a lethal inoculation of T. cruzi. Again, the
-GalCer-treated group exhibited a decreased parasitemia (Fig. 1b, p < 0.005). Although all mice in both
groups died, the -GalCer-treated group trended toward longer
survival (Fig. 1c; log rank, p = 0.09). In
addition, BALB/c mice were administered -GalCer 1 day before a
sublethal inoculum of T. cruzi, and again the
-GalCer-treated mice demonstrated reduced parasitemia (Fig. 1d, p < 0.001). Together these experiments
indicate that -GalCer treatment before T. cruzi infection
decreases parasitemia.
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-GalCer protection
To demonstrate that the protective effect of -GalCer was
dependent on NKT cells expressing the V14-J281 TCR, C57BL/6 and
BALB/c mice deficient in the J281 gene, and
therefore lacking iNKT cells, were injected with -GalCer 1 day
before infection with T. cruzi (24). Neither
strain of iNKT cell-deficient mice treated with -GalCer was
protected (Fig. 2, a,
p = 0.478, and b, p =
0.116). These data indicate that the -GalCer protection requires
iNKT cells.
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is required for -GalCer protection
When iNKT cells are stimulated with -GalCer, they can secrete
both IFN- and IL-4 (21). IFN- mediates the
protective effect of -GalCer administration against infection with
C. neoformans and Plasmodium species (19, 20). Endogenous IFN- is critical for protection against
T. cruzi (29, 30) and treatment with exogenous
IFN- can improve the protective response (31). These
data suggest that -GalCer protection against T. cruzi is
dependent on iNKT cell-derived IFN- and that a decrease in
parasitemia due to -GalCer treatment would be lost in
IFN--/- mice. C57BL/6
IFN--/- mice were treated with 1 µg of
-GalCer or diluent 1 day before infection with T. cruzi.
Parasitemia became detectable in both groups of mice on day 10 of
infection and increased until all of the mice died (Fig. 3a). Surprisingly, the
-GalCer-treated group demonstrated higher parasitemia (Fig. 3a, p < 0.01). This experiment was repeated
with a 5-µg dose of -GalCer and a very similar result was observed
(Fig. 3b, p < 0.05). The earlier
parasitemia in the -GalCer-treated groups indicate that IFN- is
required for the -GalCer protection and, furthermore, that in the
absence of IFN-, -GalCer stimulation of iNKT cells increases
susceptibility to T. cruzi. This increased susceptibility
could be caused by the -GalCer-stimulated production of IL-4 in the
absence of IFN-.
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-/- -GalCer-treated mice, groups of
IFN--/- mice were treated as follows: one
group received diluent only; one group received -GalCer in diluent;
and a third group received -GalCer in diluent and an Ab that
neutralizes IL-4 (11B11). One day later, all three groups were infected
with T. cruzi. The anti-IL-4 Ab reversed the
susceptibility of the IFN--/- mice treated
with -GalCer (Fig. 3
c). These data argue that in
IFN--/- mice, -GalCer administration
stimulates iNKT cells to secrete IL-4 that causes earlier parasitemia
(Fig. 3c; -GalCer vs diluent or -GalCer-11B11,
p 
0.01; -GalCer-11B11 vs diluent,
p = 0.316).
IL-12 is not required for -GalCer protection
IL-12 is critical during T. cruzi infection for
protective proinflammatory responses and can stimulate iNKT cell
responses, suggesting that IL-12 could be involved in the
-GalCer-mediated protection against T. cruzi
(9, 32). To explore this possibility,
IL-12-/- mice were treated with -GalCer or
diluent and infected with T. cruzi. The -GalCer-treated
group had reduced parasitemia (Fig. 4a) and increased survival
(Fig. 4b, log rank, p < 0.005), arguing
that the -GalCer protection is independent of IL-12 and is mediated
by -GalCer stimulation of the iNKT cell TCR.
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-GalCer treatments are not protective
Multiple administrations of -GalCer promote Th2 responses
(21). Therefore, we hypothesized that multiple -GalCer
treatments before T. cruzi infection would not be
protective. Thus, C57BL/6 mice received -GalCer on days 7, 4, and 1,
or only on day 1, before infection with a lethal dose of T.
cruzi. As expected mice treated with a single dose of -GalCer
had decreased parasitemia compared with control-treated mice (Fig. 5a, p <
0.05). The mice treated with three doses of -GalCer and the
diluent-treated mice had similar parasitemia (Fig. 5a;
p = 0.783). This experiment was repeated in BALB/c mice
with a sublethal inoculation and similar results were observed (Fig. 5b; p < 0.005 comparing one-dose
-GalCer treated and diluent treated, and p = 0.432,
comparing three-dose -GalCer treated and diluent treated).
The experiment in C57BL/6 mice was repeated with a sublethal inoculum
of T. cruzi, and again the mice receiving multiple doses of
-GalCer had similar parasitemia as the control mice receiving
diluent alone (Fig. 5c, p = 0.426), further
suggesting that the mice treated with three doses of -GalCer had a
similar antiparasitic response as the diluent-treated mice. These data
argue that different treatment regimens of -GalCer can be used to
increase or decrease proinflammatory responses during T.
cruzi infection.
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-GalCer treatments on the Ab response
The different -GalCer treatments (one dose vs three doses)
before T. cruzi infection altered subsequent parasitemia,
probably by altering iNKT cell IFN- and IL-4 responses and
downstream effector cell responses. To further investigate whether
the different -GalCer treatments affected the subsequent
CD4+ T cell and Ab responses, we investigated the
IgG2a Ab response (promoted by Th1 IFN-) and the IgG1 Ab response
(promoted by Th2 IL-4) to a T. cruzi surface protein, the
SA85-1.1 protein. Previous studies have demonstrated that during
T. cruzi infection a robust IgG response to this protein
occurs (5).
Although not significant, treatment with a single dose of -GalCer
reduced both the IgG2a response and the IgG1 response (Fig. 5d). In contrast, the multiple dose regimen of -GalCer
did not affect the IgG2a response, and modestly increased the IgG1
response, compared with diluent-treated mice (Fig. 5d).
Thus, although a single -GalCer treatment appears to reduce
parasitemia during T. cruzi infection by augmenting IFN-
production, it does not appear to augment anti-parasite IgG2a Ab
responses. Rather, the data suggest that the one-dose -GalCer
treatment, by reducing parasitemia and probably the number of chronic
phase persistent parasites and parasite Ags, might then diminish
stimulation of the chronic phase anti-parasitic Ab responses.
Multiple -GalCer treatments cause failure to thrive
We also analyzed morbidity by monitoring the weight of C57BL/6
mice that were infected with a sublethal inoculum of T.
cruzi (Fig. 5, c and d). During the fourth
week of the infection, after the parasitemia has resolved, the
three-dose -GalCer-treated mice demonstrated poor weight gain
compared with the diluent-treated and one-dose -GalCer-treated mice
(Fig. 5e, p < 0.01 vs diluent-treated and
one-dose -GalCer-treated mice for times after day 36 of infection).
Although the one-dose -GalCer-treated mice appear to gain more
weight than the diluent-treated mice, these differences are not
statistically significant. Taken together, these data argue that
although the immune responses of the three-dose -GalCer-treated mice
and the diluent-treated mice are equally capable of controlling the
acute phase parasitemia, these treatments differentially affect the
mice. We suggest that the three-dose -GalCer treatment is less
effective at controlling T. cruzi persistence during the
chronic phase that then causes poor weight gain.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-GalCer and related glycolipids can
modulate iNKT cell responses (12, 19, 20, 21, 22, 23, 33, 34). We
recently demonstrated that during T. cruzi infection iNKT
cells provide acute phase protection and augment some aspects of the
chronic phase proinflammatory response (5). Together,
these data suggest that glycolipid treatments could be used to augment
the protective iNKT cell response and to limit pathologic chronic
inflammatory iNKT cell responses that occur during T. cruzi
infection. To begin to explore these possibilities, we treated either
C57BL/6 or BALB/c mice with -GalCer before T. cruzi
infection. A single dose of -GalCer resulted in an iNKT
cell-dependent reduction in parasitemia (Figs. 1 and 2). These data
indicate that a single dose of -GalCer is protective for mice of
diverse genetic backgrounds and different susceptibilities to T.
cruzi infection. The protection following -GalCer treatment
required IFN- but not IL-12 (Figs. 3 and 4). In contrast, treatment
with multiple doses of -GalCer, a treatment that increases Th2
responses (21) and was not expected to be protective, did
not reduce parasitemia (Fig. 5). However, treatment with multiple doses
of -GalCer unexpectedly caused poor weight gain (Fig. 5e). These data indicate that -GalCer might be used to
modify the immune response to T. cruzi and the outcome of
chronic infection. The data argue that some -GalCer treatments may
be harmful and increase morbidity. On the other hand, further
examination of -GalCer treatment regimens and -GalCer analogs may
lead to regimens that can increase protective responses and diminish
pathologic responses. In addition, these data suggest that
environmental exposures that stimulate an individual’s iNKT cells
before and during T. cruzi infection might affect the
outcome of the infection.
iNKT cells can be stimulated directly by IL-12 (9, 24) and
can stimulate APCs to produce IL-12 (35, 36). In this
study, -GalCer-treated IL-12-/- mice
exhibited lower parasitemia and prolonged survival compared with
diluent-treated IL-12-/- mice (Fig. 4), arguing
that the antiparasitic effect of -GalCer does not require IL-12.
However, because IL-12-/- mice die rapidly we
cannot exclude the possibility that IL-12 may participate in aspects of
the protective response.
IFN- is critical to control T. cruzi infection (29, 30). Protection by -GalCer during both C.
neoformans and Plasmodium infection is dependent on
IFN- (19, 20). Therefore, we expected -GalCer
protection against T. cruzi to be dependent upon IFN-,
but were surprised that in -GalCer-treated
IFN--/- mice the parasitemia was increased
(Fig. 3). Our data argue that this increased susceptibility was due to
iNKT cell IL-4 production in the absence of IFN- (Fig. 3c).
How the -GalCer-stimulated IFN- provides protection remains
unclear. The cellular target of iNKT cell-derived IFN- was not
examined in this report, but it has been demonstrated that B cells, T
cells, macrophages, and NK cells are all activated as a consequence of
-GalCer treatment (37). We hypothesize that macrophages
and other phagocytic cells are activated by iNKT cell-derived IFN-
and, rather than being permissive for parasite replication, they become
trypanocidal.
It is unusual for T. cruzi infection of humans to result in
death during the acute phase. Rather, most morbidity and mortality is
caused by the chronic inflammatory response (1). Some
reports argue that the greater the acute phase parasitemia, then the
greater the chronic inflammation and pathology (3, 4). If
this is correct, then a treatment with -GalCer that limits
parasitemia (Fig. 1) will reduce chronic inflammatory pathology. It is
possible, however, that the augmented acute phase iNKT cell response,
despite the decrease in parasitemia, may cause a more self-damaging
chronic inflammatory response. The improved weight gain in mice treated
with -GalCer as compared with those treated with diluent argues that
the decreased parasitemia leads to decreased chronic inflammation and
decreased morbidity (Fig. 5e).
In contrast to mice treated with a single dose of -GalCer, our data
reveal that mice treated with multiple doses fail to gain weight after
resolution of parasitemia (Fig. 5). The mechanism of this failure to
thrive is unclear. We have investigated liver injury by measuring serum
GPT levels, and these studies suggest that during infection liver
injury is similar in the three groups of mice (data not shown). During
T. cruzi infection, IL-10 restricts proinflammatory
responses (38, 39). Furthermore, it was recently
demonstrated that IL-10 facilitates the persistence of the
intracellular parasite Leishmania major (40).
It is possible that treatment with multiple doses of -GalCer
promotes chronic phase Th2 responses involving IL-4 and IL-10 that
control T. cruzi less well (Fig. 5d). The
increased Th2 cytokines may then lead to increased tissue parasite
burden, increased chronic inflammation, and thus increased TNF-
production that results in poor weight gain (41, 42).
Additional studies are required to determine how the -GalCer
treatments affect weight gain.
Taken together, our data suggest that in mice the chronic inflammation
of T. cruzi infection may be optimally reduced with a single
dose of -GalCer before infection and multiple doses after resolution
of the acute phase. This treatment could limit parasitemia and parasite
tissue burden and blunt the chronic inflammatory response. Another
approach may be to treat, during the chronic phase, with -GalCer
analogs that specifically promote Th2 responses that will limit the
pathologic inflammatory responses (12). Miyamoto et al.
(12) recently described an -GalCer analog, OCH,
that preferentially stimulates iNKT cell IL-4 secretion and protects
against experimental autoimmune encephalomyelitis. -GalCer and its
analogs may prove valuable for the treatment of Chagas disease.
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Acknowledgments |
|---|
-GalCer and Drs. Toshinori Nakayama and Masaru
Taniguchi (Chiba University School of Medicine) for providing
J281-/- mice. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Malcolm S. Duthie, Infectious Disease Research Institute, 1124 Columbia Street, No. 600, Seattle, WA 98104. E-mail address: mduthie{at}idri.org
3 Abbreviations used in this paper: iNKT, invariant V14 NKT; -GalCer, -galactosylceramide.
Received for publication February 14, 2002. Accepted for publication April 3, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14 NKT cells. Semin. Immunol. 12:543.[Medline]
- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9:345.[Medline]
14 NKT cells by glycosylceramides. Science 278:1626.14 NKT cells play a crucial role in an early stage of protective immunity against infection with Leishmania major. Int. Immunol. 12:1267. intermediate cells increase during experimental malaria infection and are able to exhibit inhibitory activity against the parasite liver stage in vitro. J. Immunol. 164:1463.14+ NK T cells associated with disease development in autoimmune-prone mice. J. Immunol. 156:4035.[Abstract]
24JQ T cells in type 1 diabetes. Nature 391:177.[Medline]
24JQ antigen receptor in patients with systemic sclerosis. J. Exp. Med. 182:1163.14+ natural killer T cells by -galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans. Infect. Immun. 69:213.-Galactosylceramide-activated V14 natural killer T cells mediate protection against murine malaria. Proc. Natl. Acad. Sci. USA 97:8461.-galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur. J. Immunol. 29:2014.[Medline]
-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nat. Med. 7:1057.[Medline]
-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nat. Med. 7:1052.[Medline]
14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623.-galactosidase. Infect. Immun. 67:403., macrophage activation, and murine host defense against acute infection with Trypanosoma cruzi. J. Infect. Dis. 163:912.[Medline]
is required for resistance to acute Trypanosoma cruzi infection in mice. J. Immunol. 146:3626.[Abstract]
induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections. J. Immunol. 140:4342.[Abstract]
-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype. J. Immunol. 163:2373.14 NK T cells. J. Immunol. 166:662.-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J. Exp. Med. 189:1121.14+CD4+NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system. J. Immunol. 163:93.-mediated toxic shock in Trypanosoma cruzi-infected interleukin 10-deficient mice. Infect. Immun. 68:4075., but not by anti-IL-6 or anti-IFN- antibodies. Parasite Immunol. 17:561.[Medline]
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