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The Journal of Immunology, 2002, 168: 3135-3139.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Susceptibility to the Larval Stage of the Helminth Parasite Taenia crassiceps Is Mediated by Th2 Response Induced Via STAT6 Signaling1

Miriam Rodriguez-Sosa*,{dagger}, John R. David{dagger}, Rafael Bojalil*, Abhay R. Satoskar{dagger},{ddagger} and Luis I. Terrazas2,*,{dagger}

* Department of Immunology, Instituto Nacional de Cardiologia "Ignacio Chavez," Mexico, D.F. Mexico; {dagger} Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and {ddagger} Department of Microbiology, Ohio State University, Columbus, OH 43210


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Using STAT6-/- BALB/c mice, we analyzed the role of STAT6-induced Th2 response in determining the outcome of murine cysticercosis caused by the helminth parasite Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response; produced high levels of IgG1, IgE, IL-4, as well as IL-13; and remained susceptible to T. crassiceps. In contrast, similarly infected STAT6-/- mice mounted a strong Th1-like response; produced high levels of IgG2a, IL-12, IFN-{gamma}, as well as nitric oxide; and efficiently controlled T. crassiceps infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to T. crassiceps and, furthermore, that unlike the case in most helminths, immunity against T. crassiceps is mediated by a Th1-like rather than Th2-like response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Cysticercosis is a helminth infection caused by the larvae of the cestode Taenia solium, affecting humans and pigs. This disease is considered a public health problem in South America and Asia (1) but has been extended in the past few years to developed countries as shown by case reports published more frequently (2, 3). Cysticercosis in humans results from ingestion of Taenia eggs from excreta in the environment. Although cysticerci in muscle may be relatively symptomless, those in brain cause neurocysticercosis, which may clinically manifest as seizures, hydrocephalus, aseptic meningitis, and altered mental status (1, 3).

In the experimental model of murine cysticercosis, infection of inbred mice with Taenia crassiceps induces a strong Th2-like response similar to that observed after infection with helminths such as Nippostrongylus brasiliensis and Trichuris muris (4). Although it is widely accepted that Th2-like response mediates protective immunity against most helminths (5), its role in mediating protection against murine cysticercosis is not clear (6).

Previous studies have found that although T. crassiceps-infected mice develop a Th1-like response during the early phase of infection, they eventually develop a Th2 response that is associated with an increase in parasite loads (7). Furthermore, one study found that administration of IFN-{gamma}-neutralizing Abs to T. crassiceps-infected mice during the early phase of infection rendered them more susceptible to cysticercosis (8). These findings suggest that whereas Th2-type response may be involved in mediating susceptibility, Th1-type response may play a role in the development of protective immunity against cysticercosis.

Recent studies using STAT6-/- mice have shown that the STAT6-mediated IL-4/IL-13 signaling pathway is critical for Th2 differentiation (9, 10, 11). For example, STAT6-/- mice fail to mount a significant Th2 response and cannot control worm burdens after infection with gastrointestinal helminth parasites (12, 13). Conversely, STAT6-/- mice develop a Th1-like response and control infections caused by intracellular protozoan parasites such as Leishmania mexicana and Trypanosoma cruzi (14, 15), indicating that the STAT6-mediated signaling pathway inhibits development of protective immunity by inhibiting Th1 development.

The purpose of this study was to determine the role of a Th2-type response induced via STAT6-mediated signaling in the outcome of murine cysticercosis caused by the helminth T. crassiceps. To approach this question, we compared the course of T. crassiceps infection in STAT6-/- BALB/c mice with that in wild-type BALB/c mice. In addition, we analyzed the Ab profiles in sera, cellular responses, and cytokine profile in both spleen cells and peritoneal macrophages. Our data demonstrate that the Th2-type response induced via the STAT6-signaling pathway mediates susceptibility in cysticercosis. They also demonstrate that in the absence of STAT6-mediating signaling, susceptible BALB/c mice develop a Th1 response and control T. crassiceps infection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

Six- to 8-wk-old female STAT6-/- and STAT6+/+ mice on a genetic BALB/c background were purchased from The Jackson Laboratory Animal Resources Center (Bar Harbor, ME), and maintained in the specific pathogen-free facilities at Harvard School of Public Health animal facilities in accordance with institutional guidelines.

Parasites and infection

Metacestodes of T. crassiceps were harvested under sterile conditions from the peritoneal cavity of female BALB/c mice after 2–4 mo of infection. Mice were infected by i.p. injection with 20 small nonbudding cysticerci and sacrificed at wk 2, 4, 8, and 12 postinfection. Parasites were harvested from the peritoneal cavity and counted.

Cell preparations, culture conditions, and cytokine assays

Spleen cells were obtained and cultured as described previously (7). Briefly, single-cell suspensions were prepared in RPMI 1640 supplemented with 10% FBS, 100 U of penicillin/streptomycin, 2 mM glutamine, 25 mM HEPES buffer, and 1% nonessential amino acids (all from Life Technologies, Gaithersburg, MD). Erythrocytes were lysed, and viable cells were adjusted (3 x 106 cells/ml); 100 µl/well were placed into 96-well flat-bottom culture plates (Costar, Cambridge, MA) and stimulated with T. crassiceps Ag (TcAg3; 25 µg/ml) at 37°C for 96 h. Eighteen hours before culture termination, 0.5 µCi/well [3H]thymidine (NEN, Boston, MA) were added. Cells were harvested and counted using a beta plate counter. Values are represented as cpm.

Supernatants from these cultures were analyzed for IFN-{gamma}, IL-4 (BD PharMingen, San Diego, CA) and IL-13 (R&D Systems, Minneapolis, MN) production by ELISA.

Cytokine and nitric oxide production by peritoneal macrophages.

Peritoneal exudate cells (PECs) were obtained from mice at 2, 4, 8, and 12 wk after T. crassiceps infection. PECs were adjusted to 5 x 106/ml in RPMI supplemented and plated in 6-well plates (Costar). After 2 h at 37°C and 5% CO2, nonadherent cells were removed, and adherent cells were gently scraped using cold PBS and readjusted to 1 x 106/ml. Viability at this point was >90%. These cells constituted >90% of macrophages according to FACS analysis (F4/80+). One milliliter was plated, and cell activation was performed in 24-well plates (Costar) with LPS (5 µg/ml; Escherichia coli 111:B4; Sigma Aldrich, St. Louis, MO) followed by incubation for 48 h. IL-6, IL-12 (BD PharMingen), and nitric oxide (Griess reaction) were examined in supernatants. Total PECs were analyzed by cytospin preparation stained with Wright-Giemsa stain (Sigma Aldrich), and 400 cells were counted by slide.

Ab ELISA

Blood was collected from tails of T. crassiceps-infected STAT6+/+ and STAT6-/- mice. Ag-specific IgG1 and IgG2a levels were determined by ELISA as previously described (16). Results are expressed as the endpoint titer. Total IgE production was detected by Opt-ELISA (BD PharMingen).

Statistical analysis.

Comparisons between STAT6+/+ and STAT6-/- groups considered in this work were made using Student’s unpaired t test. A value of p < 0.05 was considered significant. The statistical significance of the sera titers were determined by nonparametric tests using the Mann-Whitney U-Wilcoxon rank test.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
It is widely accepted that the Th2-like response induced via the STAT6-mediated signaling pathway (through IL-4/IL-13 receptors) plays a critical role in mediating protective immunity against most helminths (17, 18, 19). For example, STAT6-mediated signaling promotes protective immunity against Trichinella spiralis (13) and N. brasiliensis (12). In the present study, both STAT6+/+ and STAT6-/- mice showed a progressive increase in the parasite numbers in their peritoneal cavities and displayed comparable parasite burdens at 2 and 4 wk after infection with T. crassiceps (Fig. 1Go). Interestingly, as infection progressed, parasite burdens increased significantly in STAT6+/+ mice as compared with STAT6-/- mice that successfully controlled the infection by wk 12 postinfection (Fig. 1Go). These findings demonstrate that STAT6-mediated signaling pathway is involved in pathogenesis of T. crassiceps infection.



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  		FIGURE 1. STAT6-/- mice efficiently control T. crassiceps infection. Course of i.p. T. crassiceps infection in STAT6-/- (•) and STAT6+/+ ({circ}) mice after infection with 20 cysticerci. Data are expressed as the mean ± SE of 4 mice per group. *, p < 0.01 comparing STAT6-/- vs STAT6+/+ at the same time point. Similar results were observed in three independent experiments.

 
Previous studies have demonstrated that the STAT6-mediated signaling pathway prevents development of protective immunity against intracellular parasites such as L. mexicana and Trypanosoma cruzi by inhibiting Th1 development (14, 15). Furthermore, we previously found that mice treated with IFN-{gamma} and IL-2 during the early course of T. crassiceps infection restrict the parasite growth, suggesting that the Th1 response may mediate protective immunity against this parasite (8). Therefore, we measured levels of Th1-associated IgG2a as well as Th2-associated IgG1 and IgE Abs in STAT6-/- and STAT6+/+ mice at different time points after infection with T. crassiceps. During wk 2 and 4 postinfection, T. crassiceps-infected STAT6+/+ and STAT6-/- mice displayed comparable titers of TcAg-specific IgG1, but IgG2a Abs were significantly higher in STAT6-/- mice as early as 4 wk after infection (Fig. 2Go, a and b). By wk 8 postinfection and thereafter, STAT6+/+ mice displayed significantly higher titers of TcAg-specific IgG1 than did STAT6-/- mice, which produced significantly more TcAg-specific IgG2a (Fig. 2Go, a and b). Similar differences were observed in the levels of total IgG1 and IgG2a (data not shown). Although Th2-associated IgE has been shown to play a role in mediating immunity against helminths (20, 21), we found that T. crassiceps-infected STAT6-/- mice efficiently controlled parasite burdens despite producing significantly lower levels of IgE as compared with similarly infected STAT6+/+ mice, suggesting that IgE may have a limited role in mediating protective immunity against T. crassiceps (Fig. 2Goc).



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  		FIGURE 2. Kinetics of Ab production during T. crassiceps infection in STAT6-/- (•) and STAT6+/+ ({circ}) mice. a, Anti-T. crassiceps-specific IgG2a; b, anti-T. crassiceps-specific IgG1; c, total IgE. Values are the mean ± SE (n = 4 animals) and are representative of three independent experiments. *, p < 0.05 comparing STAT6-/- vs STAT6+/+ at the same time point.

 
The spleen cells from T. crassiceps-infected STAT6+/+ and STAT6-/- mice displayed different patterns of proliferative responses after in vitro stimulation. Whereas TcAg-stimulated splenocytes from STAT6+/+ mice displayed higher proliferative responses during the early phase of infection, those from STAT6-/- mice developed significantly stronger responses in chronic infections as compared with wild-type mice (Fig. 3Goa). At wk 4, 8, and 12 postinfection, TcAg-stimulated spleen cells from STAT6-/- mice produced greater levels of IFN-{gamma} than did those from STAT6+/+ mice (Fig. 3Gob). In contrast, as the infection progressed, TcAg-stimulated spleen cells from STAT6+/+ mice produced significantly more IL-4 and IL-13 than those from STAT6-/- mice, which produced low levels of these cytokines only during early phase of infection (Fig. 3Go, c and d), demonstrating the inability of these mice to maintain a sustained Th2-type response (10, 11). Interestingly, higher levels of Th2-type cytokines in STAT6+/+ mice were associated with higher parasite loads. Taken together, these findings suggest that unlike other helminths, the Th2-type response is not essential for mediating protective immunity against T. crassiceps. They also indicate that Th2-type response may be detrimental for cysticercosis. Moreover, others using radiation-attenuated vaccine and IL-12 as an adjuvant against Schistosoma have shown that a Th1-like response can mediate protective immunity in this model (22, 23).



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  		FIGURE 3. Kinetics of in vitro proliferative response and cytokine production by TcAg-stimulated spleen cells from STAT6-/- ({blacksquare}) and STAT6+/+ ({square}) mice. a, Ag-specific proliferative response of splenocytes (96 h); b, specific IFN-{gamma}; c, specific IL-4; d, specific IL-13 production by splenocytes after 72 h in vitro stimulation with TcAg (25 µg/ml). Data are expressed as in Fig. 2Go.

 
Several studies have demonstrated that macrophages play a critical role in immunity against many intracellular pathogens by their ability to secrete Th1-inducing cytokines such as IL-12 and IL-18 as well as produce NO that is not only microbicidal (24) but also cytotoxic to larvae of Schistosoma (25). Although peritoneal macrophages do not adhere in situ to T. crassiceps (C. Larralde, unpublished observations), we hypothesized that these cells may be involved in mediating protective immunity against T. crassiceps metacestodes in STAT6-/- mice by secreting Th1-inducing cytokines such as IL-12 and by releasing NO. Hence, we analyzed IL-6, IL-12, and NO production by adherent peritoneal macrophages from T. crassiceps-infected mice. Macrophages from STAT6+/+ mice obtained during the early phase of infection (2 wk) produced levels of IL-12 similar to those from STAT6-/- mice (Fig. 4Goa). In contrast, IL-6 was detected in lower levels in the same supernatants (Fig. 4Gob). As infection progressed, macrophages from chronically infected STAT6+/+ mice produced increased levels of IL-6 (Fig. 4Gob), but low levels of IL-12 (Fig. 4Goa). These patterns of macrophage response were opposed to those observed in STAT6-/- mice, which showed a low production of IL-6 but a sustained and significantly higher production of IL-12 in late infections (Fig. 4Go, a and b). NO production was maintained in steady levels until the 4th wk after infection in STAT6+/+ mice; however, as the infection became more chronic (8–12 wk), the NO levels dropped significantly (Fig. 4Goc). In contrast, macrophages from T. crassiceps-infected STAT6-/- mice produced sustained levels of NO throughout the course of infection (Fig. 4Goc). Taken together, these observations suggest that the STAT6 signaling pathway mediates susceptibility to T. crassiceps, at least in part, by inhibiting macrophage IL-12 and NO production. This is supported by previous studies demonstrating that IL-4 and IL-13 inhibit production of IL-12 and NO from macrophages in a STAT6-dependent manner (26, 27). Indeed, reduced IL-6 production in STAT6-/- mice may also contribute to enhancement of Th1 response, given that IL-6 has been shown to play a critical role in differentiation of IL-4 producing CD4+ T cells (28).



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  		FIGURE 4. Peritoneal macrophages from STAT6-/- and STAT6+/+ T. crassiceps-infected mice display different responses. Macrophages were obtained at different time points after infection and stimulated with LPS (5 µg/ml) during 48 h; supernatants were analyzed for IL-12p70 (a), IL-6 (b), and NO (c) production. Data are expressed as in Fig. 2Go.

 
Eosinophils are considered one of the most efficient effectors cells in several helminth parasitic diseases (21, 29). Therefore, we evaluated the inflammatory infiltrate in the peritoneal cavity of STAT6-/- and STAT6+/+ mice in early and late infections. At 2 wk postinfection, STAT6+/+ mice recruited up to 11 ± 1.9% of eosinophils, whereas STAT6-/- recruited significantly lower percentages (1 ± 0.2%; p < 0.05). At late infection (8 wk), STAT6+/+ mice maintained a higher recruitment of eosinophils, rising to 18 ± 1.8%. Conversely, STAT6-/- did not present eosinophils at all (<1%) by this time; instead, they had an increased infiltration of lymphocytes as compared with STAT6+/+ mice (25 ± 2.5% vs 7 ± 1.5%, respectively) but similar numbers of macrophages, suggesting a role for these cells in the elimination of the parasite and at the same time ruling out the eosinophils as potential effector cells in murine cysticercosis. These findings oppose the dogma that eosinophils are the key cells that play a critical role eliminating helminths (7, 20, 21, 29). In contrast, our data favor a possible active participation of macrophages in eliminating T. crassiceps, perhaps by producing NO. Additionally, we analyzed other cell populations of the peritoneal cavity throughout the infection. Basophils/mast cells were detected in low percentages in STAT6+/+ mice at early infections (1.2 ± 0.6%), and lower in late ones (0.2 ± 0.2%). STAT6-/- mice recruited 0.4 ± 0.1% at wk 2 and 0.6 ± 0.4% at late infection. Both STAT6+/+ and STAT6-/- mice had comparable numbers of neutrophils (2 ± 0.4% and 3.5 ± 0.9%) throughout the infection. These findings suggest that other effector cells such as basophils/mast cells and neutrophils may not play a significant role in mediating resistance against T. crassiceps infection in STAT6-/- mice.

In conclusion, STAT6-/- BALB/c mice mount a strong Th1-like response; produce high levels of IL-12, IFN-{gamma}, and NO; and efficiently control T. crassiceps infection. In contrast, STAT6+/+ BALB/c mice develop a predominant Th2-like response associated with high levels of IL-4, IL-13, IgG1, IgE, and eosinophilia and display significantly higher parasite loads. Our findings support the hypothesis that STAT6-mediated signaling is critical for the suppression of the Th1 responses required for controlling murine cysticercosis and also suggest that Th2 cytokines favor the development of susceptibility during cysticercosis infection via STAT6 activation.


   Footnotes
 
1 This work was partially supported by Grant 31102-M from Consejo Nacional de Ciencia y Technología-Mexico. M.R.S. and L.I.T. are recipients of fellowships from Consejo Nacional de Ciencia y Technología-Mexico. Back

2 Address correspondence and reprint requests to Dr. Luis I. Terrazas, Department of Immunology, Instituto Nacional de Cardiologia "Ignacio Chavez," Mexico, D.F. Mexico 14080. E-mail address: terlui{at}cardiologia.org.mx Back

3 Abbreviations used in this paper: TcAg, Taenia crassiceps soluble Ag; PEC, peritoneal exudate cell. Back

Received for publication December 27, 2001. Accepted for publication February 7, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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