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The Journal of Immunology, 2000, 164: 2046-2052.
Copyright © 2000 by The American Association of Immunologists

Stat6 Signaling Promotes Protective Immunity Against Trichinella spiralis Through a Mast Cell- and T Cell-Dependent Mechanism1

Joseph F. Urban, Jr.*, Lisa Schopf*, Suzanne C. Morris{dagger}, Tatyana Orekhova{dagger}, Kathleen B. Madden{ddagger}, Catherine J. Betts§, H. Ray Gamble*, Colleen Byrd*, Deborah Donaldson, Kathryn Else§ and Fred D. Finkelman2,{dagger}

* U.S. Department of Agriculture, Beltsville, MD, 20705; {dagger} Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 and Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220; {ddagger} Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; § University of Manchester, Manchester, United Kingdom; and Genetics Institute, Cambridge, MA 02140


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Studies in mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis demonstrated that IL-4/IL-13 activation of Stat6 suppresses development of intestinal mastocytosis and does not contribute to IL-4/IL-13 production, but is still essential for parasite expulsion. Because expulsion of another gastrointestinal nematode, Trichinella spiralis, unlike N. brasiliensis expulsion, is mast cell dependent, these observations suggested that T. spiralis expulsion would be Stat6 independent. Instead, we find that Stat6 activation by IL-4/IL-13 is required in T. spiralis-infected mice for the mast cell responses that induce worm expulsion and for the cytokine responses that induce intestinal mastocytosis. Furthermore, although IL-4 induces N. brasiliensis expulsion in the absence of B cells, T cells, and mast cells, mast cells and T cells are required for IL-4 induction of T. spiralis expulsion. Thus, Stat6 signaling is required for host protection against N. brasiliensis and T. spiralis but contributes to expulsion of these two worms by different mechanisms. The induction of multiple effector mechanisms by Stat6 signaling provides a way for a cytokine response induced by most gastrointestinal nematode parasites to protect against most of these parasites, even though different effector mechanisms are required for protection against different nematodes.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Recent studies of mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis demonstrated that expulsion of this parasite is dependent on 1) the secretion of IL-13 and, to a lesser extent, IL-4; 2) the binding of these cytokines to receptors that contains the IL-4R {alpha}-chain; and 3) the activation of the transcription molecule, Stat6 (1, 2). The Stat6 requirement for N. brasiliensis expulsion is not related to Stat6 effects on B cells, T cells, or mast cells because none of these cell types is required for IL-4-induced worm expulsion (1, 3, 4). Furthermore, N. brasiliensis-induced type 2 cytokine production, IgG1 secretion, and eosinophil responses are all normal or increased, and mast cell responses are greatly increased, in Stat6-deficient mice (1). These observations, along with demonstration of roles for IL-4 and/or IL-13 in protective immunity against other gastrointestinal parasites, such as Trichuris muris (5, 6) and Heligmosomoides polygyrus (7), raised the possibility that Stat6 signaling by one or both of these cytokines is a universal requirement for host protection against gastrointestinal nematode parasites.

Against this hypothesis was strong evidence that mast cells play a decisive role in host protection against at least three gastrointestinal nematode parasites: Trichinella spiralis, Strongyloides ratti, and Strongyloides venezuelensis (8, 9, 10, 11, 12, 13). Evidence that 1) expulsion of each of these parasites is severely impaired in mast cell-deficient mice; 2) expulsion of Strongyloides is impaired in mice deficient in the mast cell-stimulating cytokine, IL-3 (8); and 3) exogenous IL-3 stimulates expulsion of S. ratti and T. spiralis (10, 14) raised the possibility that IL-4 and IL-13 might have little role in protective immunity against these parasites, unless these cytokines were needed to promote the production of Abs that stimulate mast cell activation and degranulation. In fact, evidence that Stat6 signaling suppresses mast cell responses in mice infected with N. brasiliensis (1) raised the possibility that Stat6 deficiency might enhance protective immunity against T. spiralis and Strongyloides species.

To examine these possibilities, we studied the roles of IL-4, IL-13, IL-4R {alpha}-chain, and Stat6 in worm expulsion during a primary infection of mice with one of these parasites, T. spiralis. Surprisingly, the results of these studies demonstrated that IL-4, IL-13, IL-4R{alpha}, and Stat6 are all important for protective immunity against this parasite. However, in contrast to results observed in mice infected with N. brasiliensis, Stat6 signaling was found to be important for the induction of type 2 cytokine production and intestinal mastocytosis in T. spiralis-infected mice.


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

Female BALB/c mice and athymic nude male mice were purchased from the Small Animals Division of the National Cancer Institute (Frederick, MD). Mice heterozygous for a defective IFN-{gamma} gene (15) and bred onto a BALB/c background were originally obtained from Dr. Richard Locksley (San Francisco, CA). Mice homozygous for the defective or wild-type IFN-{gamma} gene were bred from these heterozygotes at the Cincinnati Veterans Administration Medical Center Animal Facility. Homozygous IL-4R{alpha}-deficient (16) mice on a BALB/c background were obtained from Dr. Nancy Noben-Trauth (Rockville, MD). Homozygous IL-4-deficient mice on a C57BL/6 background (17) were obtained from Manfred Kopf (Freiburg, Germany). Stat6-deficient mice on a mixed 129/C57BL/6 background (18) were obtained from Dr. James Ihle (Memphis, TN). RAG2-deficient mice (19) on a C57BL/10 background were obtained from Dr. Ronald Schwartz (Bethesda, MD). Genetic background controls were bred or purchased for all mouse strains. Mice were age-, sex-, and background strain-matched with controls in all experiments.

Parasites

T. spiralis (Beltsville strain) was maintained by serial passage in female Sprague Dawley rats. First-stage larvae (L1)3 were recovered from infected muscle by pepsin-HCl (1% each) digestion of eviscerated, ground rat carcasses and were washed by settling through several changes of water. Mice were inoculated orally with 50 L1 suspended in 0.2% Bacto Agar (Difco, Detroit, MI) using an 18-gauge feeding tube. Adult worms were recovered from mice after the intestine was slit lengthwise, rinsed, and placed in HBSS for 4 h at 37°C and were counted with a dissecting microscope. Muscle larvae (L1) were recovered from infected muscle by pepsin-HCl (1% each) digestion of evicerated, ground rat or mouse carcasses and washed by settling through several changes of tap water. Larvae were counted from individual carcasses using a dissecting microscope.

Immunological reagents

Recombinant mouse IL-4 was a gift of the Schering-Plough Research Institute (Kenilworth, NJ). An IL-13 antagonist, soluble IL-13R{alpha}2-Fc (sIL-13R{alpha}2-Fc) (1), and a control human IgG Ab were gifts of Genetics Institute (Cambridge, MA). A neutralizing rat IgG1 anti-mouse IL-4 mAb, 11B11 (20), was purchased from Verax (Lebanon, NH). Hybridomas that secrete a neutralizing rat IgG1 anti-mouse IFN-{gamma} mAb (XMG-6) (21) or a control rat IgG1 mAb (GL113) were obtained from the DNAX Research Institute (Palo Alto, CA). Pairs of mAbs used for measurement of in vivo production of IL-3, IL-4, or IFN-{gamma} (see below) were also obtained from the DNAX Research Institute, with the kind assistance of Dr. Anne O’Garra and Dr. Robert Coffman. ACK-2, a blocking anti-c-kit mAb, (12), produced by Dr. S. I. Nishikawa, was obtained from Dr. Richard Grencis (Manchester, U.K.). Some mAbs were produced as ascites in pristane-primed athymic nude mice and purified by salt fractionation and ion exchange chromatography (21). Some mAbs were labeled with biotin-N-hydroxysuccinimide (Calbiochem-Behring, La Jolla, CA). Polyclonal and mAbs used for titering IgG1 and IgG2a anti-T. spiralis Ab levels in infected mice have been described (1). T. spiralis Ag used in the ELISA was prepared as previously described (22). Excretory-secretory protein was collected by culturing 5000 T. spiralis L1 per ml of DMEM supplemented with 2 mM glutamine, 10 mM HEPES buffer, 50 U penicillin/ml, and 50 µg streptomycin/ml for 18–20 h at 37°C in an atmosphere that contained 10% CO2. Culture supernatants were harvested by filtration, dialyzed against PBS, and concentrated by pressure filtration. An ELISA kit, purchased from Moredun Scientific (Penicuik, Scotland), was used to quantitate serum levels of mouse mast cell protease 1 (MMCP1).

Production and use of IL-4/anti-IL-4 mAb complexes (IL-4C)

Soluble complexes made by mixing IL-4 with the neutralizing anti-IL-4 mAb, 11B11, at a 2:1 molar ratio (1:6 weight ratio) have an in vivo half-life that is much longer than that of uncomplexed IL-4. These complexes slowly and spontaneously dissociate when administered to mice, releasing free, biologically active IL-4. This allows a single injection of IL-4C to sustain an IL-4 effect for 3–5 days (23). In experiments aimed at testing whether IL-4 can promote worm expulsion, mice were injected i.v. every 3 days with IL-4C that contained 5 µg of IL-4 and 25 µg of 11B11 (a dose previously shown to promote N. brasiliensis expulsion; Ref. 4).

Quantitation of in vivo cytokine production

The Cincinnati cytokine capture assay (CCCA) was used to monitor in vivo production of IL-3, IL-4, and IFN-{gamma}. This assay allows cytokines to accumulate in serum by "capturing" them in vivo with neutralizing IgG mAbs that inhibit their excretion, utilization, and catabolism (1, 24). The IL-4 CCCA increases the ability to detect IL-4 in serum by >1000-fold and is specific (no IL-4 response is detected in IL-4-deficient mice). To capture secreted IL-4, mice were injected i.v. with 10 µg of biotin-BVD4-1D11, a neutralizing anti-IL-4 mAb (25). Mice were bled 2–4 h later, and serum levels of IL-4-biotin-anti-IL-4 complexes were determined by ELISA using microtiter plates coated with BVD6-24G2.3 (25). This mAb recognizes an IL-4 epitope that is distinct from that recognized by BVD4-1D11. A CCCA for IFN-{gamma} was performed similarly by injecting mice with 50 µg of biotin-R46-A2 (26) and coating microtiter plate wells with AN18 (27); a CCCA for IL-3 was performed by injecting mice with 20 µg of biotin-MP2-8F8 (25) and coating microtiter plate wells with MP2-43D11 (28).

Quantitation of mucosal mastocytosis

Tissue samples from an 8- to 10-cm mid-jejunal segment from individual mice were prepared by the Swiss role technique and fixed in Carnoy’s fixative. Sections were stained with Alcian blue and safranin O and examined microscopically at a magnification of x400 (29). Alcian blue-positive, safranin O-negative cells in the lamina propria and epithelium of villi and crypts were classified as mucosal mast cells (MMC). Numbers of MMC in 50 adjacent high-power fields were recorded.

Statistical analysis

Data were analyzed using the general linear method procedure with group means compared with the Duncan’s multiple range test for variables (BMDP Statistical Software, Los Angeles, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
T. spiralis expulsion is inhibited by endogenously produced IFN-{gamma} and requires either IL-4 or IL-13 stimulation of IL-4R{alpha}

Results of earlier studies differed about whether production of type 1 or type 2 cytokines is associated with host protection against T. spiralis (30, 31) and did not directly test the in vivo effects of these cytokines on parasite expulsion. In experiments that use recombinant mice to directly examine cytokine effects on expulsion of T. spiralis, we find a clear association between type 2 cytokine production and host protection. IFN-{gamma}-deficient mice frequently expel T. spiralis more rapidly than wild-type mice (Fig. 1GoA) and, as a result, develop fewer muscle larvae after a primary infection (Fig. 1GoB). In contrast, mice that cannot respond to either IL-4 or IL-13, because they lack a functional gene for IL-4R{alpha} (a component of receptors for both cytokines; Refs. 32, 33, 34, 35), fail to clear T. spiralis adults from the gut (Fig. 1GoC) and develop increased numbers of muscle larvae (Fig. 1GoD). Both endogenously produced IL-4 and IL-13 stimulate IL-4R{alpha} sufficiently to expel T. spiralis adults: T. spiralis expulsion is normal in IL-4-deficient mice and in wild-type mice treated with an IL-13 antagonist (sIL-13R{alpha}2-Fc), while IL-13 antagonist-treated IL-4-deficient mice develop a persistent infection (Fig. 1GoE).



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  		FIGURE 1. T. spiralis expulsion can be induced by endogenously produced IL-4 or IL-13 and is inhibited by endogenously produced IFN-{gamma}. A, Wild-type or IFN-{gamma}-deficient mice on a BALB/c background were inoculated orally with 50 T. spiralis muscle larvae. Mice were sacrificed, and adult worms were counted at the time points indicated. Means and SEs are shown in this and in all subsequent figures. Five mice were used per group in this and in all subsequent experiments. B, Wild-type and IFN-{gamma}-deficient mice on a BALB/c background were inoculated with T. spiralis as above. Mice were sacrificed, and numbers of muscle larvae were determined 42 days later. C, Wild-type and IL-4R{alpha}-deficient mice on a BALB/c background were inoculated with T. spiralis as above. Mice were sacrificed 7 or 21 days after parasite inoculation, and the numbers of adult worms were determined. The decreased number of T. spiralis worms in the gut of IL-4R{alpha}-deficient mice that was seen 7 days after worm inoculation in this experiment was not consistently observed. D, Wild-type and IL-4R{alpha}-deficient mice on a BALB/c background were inoculated with T. spiralis as above. Mice were sacrificed 43 days later, and the numbers of muscle larvae were determined. E, Wild-type or IL-4-deficient mice on a C57BL/6 background were inoculated with T. spiralis as above and treated either every 2 days i.p. with 100 µg of sIL-13R{alpha}2-Fc, to neutralize IL-13, or every 4 days i.p. with 100 µg of a control (normal human IgG). Adult worms in control Ab-treated mice were counted 7, 10, and 14 days after parasite inoculation; adult worms in sIL-13R{alpha}2-Fc-treated mice were counted 14 days after parasite inoculation.

 
IL-4 stimulation of T. spiralis expulsion requires mast cells and cells of the adaptive immune system

The observations that 1) endogenously produced IL-4 stimulates T. spiralis expulsion (Fig. 1GoE) and 2) IL-4 treatment of mice deficient in B cells, T cells, and mast cells stimulates expulsion of the gastrointestinal nematode parasite, N. brasiliensis (3, 4), led us to evaluate the effects of IL-4 treatment on expulsion of T. spiralis. Increasing IL-4 levels by injecting wild-type mice with a long-acting formulation of IL-4, IL-4C (23), frequently accelerated expulsion of T. spiralis worms and decreased the accumulation of T. spiralis muscle larvae (Fig. 2GoA). However, in contrast to IL-4-induced expulsion of N. brasiliensis, IL-4C stimulation of T. spiralis expulsion is mast cell-dependent and B cell- and/or T cell-dependent mice (it has no effect in mast cell-deficient (anti-c-kit mAb-treated) mice or in B and T cell-deficient (RAG2 knockout) mice; Fig. 2GoB).



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  		FIGURE 2. Acceleration of worm expulsion by IL-4C treatment is mast cell and B or T cell dependent. A, BALB/c mice were inoculated with T. spiralis as above and injected i.v. with saline or IL-4C that contained 5 µg of IL-4 and 30 µg of anti-IL-4 mAb 1 day before worm inoculation and 2 and 5 days after inoculation. Adult worms were counted in mice sacrificed 8 days after worm inoculation, and muscle larvae were counted in mice sacrificed 41 days after worm inoculation. B, Wild-type and RAG2-deficient mice, on a C57BL/10 background, were inoculated with T. spiralis as above and treated with IL-4C that contained 5 µg of IL-4 1 day before and 2, 5, and 8 days after worm inoculation. Wild-type mice also received either 0.5 mg of an anti-mouse c-kit mAb or a control mAb i.v. 1 day before and 6 days after worm inoculation. Mice were sacrificed 11 days after worm inoculation, and the numbers of adult worms were determined. C, Sera collected 11 days after worm inoculation in the same experiment shown in B were assayed by ELISA for MMCP1 concentration.

 
To determine whether defective T. spiralis expulsion in IL-4C-treated RAG2-deficient mice was related to a mast cell degranulation defect in these mice, we compared MMCP1 serum levels (an indicator of mast cell degranulation) in T. spiralis-inoculated IL-4C-treated and untreated wild-type mice, wild-type mice in which mast cell development had been suppressed with anti-c-kit mAb and RAG2-deficient mice. IL-4C treatment was found to be unable to induce a strong MMCP1 response in either anti-c-kit mAb-treated wild-type mice or RAG2-deficient mice (Fig. 2GoC). Thus, even in the presence of IL-4, T cells and/or B cells are required to induce mast cell degranulation in T. spiralis-infected mice.

Worm expulsion and mast cell, type 2 cytokine, and IgG1 responses are Stat6 dependent in T. spiralis-inoculated mice

Prior observations that T. spiralis expulsion is mast cell dependent and that Stat6 suppresses intestinal mastocytosis and mast cell degranulation in N. brasiliensis-infected mice suggested that T. spiralis expulsion might be enhanced in Stat6-deficient mice. Contrary to this expectation, Stat6-deficient mice developed chronic infections with T. spiralis (Fig. 3GoA) and increased numbers of muscle larvae following T spiralis inoculation (Fig. 3GoB). Because the failure of Stat6-deficient mice to expel T. spiralis was surprising in view of the increased mast cell responses in Stat6-deficient, N. brasiliensis-inoculated mice (1) and the mast cell-dependence of T. spiralis expulsion (11, 12), we compared mast cell responses in wild-type and Stat6-deficient T. spiralis-infected mice. In contrast to observations made in N. brasiliensis-infected mice, intestinal MMC numbers and serum MMCP1 responses were greatly depressed in T. spiralis-inoculated, Stat6-deficient mice (Fig. 4Go, A and B).



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  		FIGURE 3. Stat6 is required for worm expulsion in T. spiralis-infected mice. A, Wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis as above. Mice were sacrificed 7 or 21 days after parasite inoculation, and the number of adult worms were determined. B, Wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis as above and injected i.v. on the day of and 8 days after parasite inoculation with 1 mg of anti-IFN-{gamma} mAb or an isotype-matched control mAb. Mice were sacrificed 42 days after parasite inoculation, and the number of muscle larvae were determined.

 


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  		FIGURE 4. Stat6 dependence of mast cell, cytokine, and IgG Ab responses in T. spiralis-inoculated mice. A, Intestinal MMC numbers were determined in wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background before T. spiralis inoculation and 14 and 35 days after inoculation. B, Serum levels of MMCP1 were determined 7 and 42 days after wild-type or Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis. Levels were <15 ng/ml in uninfected mice. C, Wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis as above. Mice were tested for IL-4 production by CCCA before worm inoculation and 8 and 11 days later and for IL-3 and IFN-{gamma} production by CCCA before worm inoculation and 11 days later. D, Wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis as above. Mice were bled 12, 14, 21, and 28 days after worm inoculation, and relative levels of serum IgG1 and IgG2a Abs to T. spiralis excretory/secretory Ag were determined by ELISA.

 
Because the injection of IL-4 stimulates a considerably larger MMC response in otherwise untreated Stat6-deficient than in wild-type mice (1), this result suggested that type 2 cytokine responses are suppressed or deviated in Stat6-deficient, T. spiralis-inoculated mice, even though they are normal in Stat6-deficient, N. brasiliensis-inoculated mice (1). Measurement of in vivo cytokine production supported this possibility: IL-4 production was suppressed 3-fold, IL-3 production was suppressed 2-fold, and IFN-{gamma} production was increased 3-fold in T. spiralis-inoculated, Stat6-deficient, as compared with wild-type mice (Fig. 4GoC). Consistent with deviation toward a type 1 cytokine response in T. spiralis-inoculated Stat6-deficient mice, serum levels of IgG1 anti-T. spiralis Ab were suppressed and IgG2a anti-T. spiralis Ab increased in Stat6-deficient mice (Fig. 4GoD).

Because IFN-{gamma} can retard T. spiralis expulsion (Fig. 1GoA) and Stat6-deficient, T. spiralis-inoculated mice develop an increased IFN-{gamma} response, we examined whether anti-IFN-{gamma} mAb treatment would restore the ability of Stat6-deficient mice to limit infection with T. spiralis, as determined by accumulation of muscle larvae. Anti-IFN-{gamma} mAb treatment only slightly corrected the increased accumulation of T. spiralis larvae in Stat6-deficient mice (Fig. 3GoB) and had no effect, in this experiment, on the number of muscle larvae in wild-type mice. Thus, increased production of IFN-{gamma} may contribute to, but is not fully responsible for, defective T. spiralis expulsion in Stat6-deficient mice.

IL-4C treatment partially restores protective immunity against T. spiralis in Stat6-deficient mice

Treatment of Stat6-deficient mice with IL-4C might be expected to restore the ability of T. spiralis-inoculated Stat6-deficient mice to expel this parasite because 1) T. spiralis expulsion is mast cell-dependent (11, 12); 2) mast cell responses are stimulated by IL-4 and suppressed by IFN-{gamma} (23, 27, 36); and 3) IL-4 production is suppressed in Stat6-deficient mice. Indeed, treatment of Stat6-deficient mice with IL-4C decreased adult worm number by a factor of 3 and muscle larva number by a factor of 2, although treated mice still retained larger numbers of adult worms and had more muscle larvae than wild-type mice and IL-4C treatment had no effect, in this experiment, on the number of muscle larvae in wild-type mice (Fig. 5GoA). The effects of IL-4C treatment on worm expulsion in Stat6-deficient, T. spiralis-inoculated mice were consistent with the ability of IL-4C treatment to partially correct the decreased MMC number and serum MMCP1 responses in these mice (Fig. 5Go, B and C). IL-4C-treated, T. spiralis-inoculated Stat6-deficient mice took longer than similarly treated wild-type mice to develop the same degree of intestinal mastocytosis (Fig. 5GoB). More importantly, peak levels of mast cell degranulation, as monitored by serum MMCP1, were considerably lower in IL-4C-treated, T. spiralis-inoculated, Stat6-deficient mice than in similarly treated wild-type mice (Fig. 5GoC). These observations are opposite to those made in mice infected with N. brasiliensis (1) and suggest that Stat6 signaling is required in T. spiralis-inoculated mice to stimulate conditions that induce mast cells to degranulate optimally.



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  		FIGURE 5. IL-4 treatment accelerates T. spiralis expulsion and partially corrects the deficient mast cell response in Stat6-deficient mice. A, Wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis as above and injected i.v. 1 day before parasite inoculation and 2, 5, 8, and 11 days after inoculation with IL-4C that contained 5 µg of IL-4. Adult worms were counted in mice sacrificed 14 days after parasite inoculation, and muscle larvae were counted in mice sacrificed 45 days after parasite inoculation. B, Wild-type and Stat6-deficient mice on a mixed 129/C57BL/6 background were inoculated with T. spiralis as above and injected i.v. with saline or with IL-4C that contained 5 µg of IL-4 on the day before parasite inoculation and 2, 5, 9, 12, and 14 days after inoculation. Mice were sacrificed 10 or18 days after worm inoculation, and intestinal MMC numbers were determined. C, Levels of MMCP1 were determined in sera obtained before parasite inoculation and at the time of mouse sacrifice from the same saline and IL-4C-treated wild-type and Stat6-deficient mice shown in B. MMCP1 levels in sera drawn from wild-type and Stat6-deficient mice 1 day before worm inoculation were 12.5 ± 6.2 and 3.3 ± 0.9 ng/ml, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results demonstrate that there are common features in the cytokine pathways that promote protective immunity against T. spiralis and N. brasiliensis even though the ultimate effector mechanisms that induce expulsion of these two gastrointestinal nematode parasites differ. Endogenous production of IFN-{gamma} suppresses T. spiralis expulsion, while production of IL-4 or IL-13 is not only essential for spontaneous expulsion, but can probably be a limiting factor in induction of expulsion, inasmuch as treatment with exogenous IL-4 frequently accelerates expulsion. Spontaneous T. spiralis expulsion also requires expression of IL-4R{alpha}, a constituent of receptors for both IL-4 and IL-13, and the IL-4R{alpha}-associated signaling molecule Stat6. All of these observations are consistent with observations made in N. brasiliensis-infected mice, with the single exception that IL-13 is more critical than IL-4 for expulsion of N. brasiliensis (1, 2), while either cytokine is sufficient to induce optimal expulsion of T. spiralis. An additional similarity between protective immunity against N. brasiliensis and T. spiralis is that both are B cell and Ig independent.

In contrast to these similarities, T. spiralis and N. brasiliensis infections differ in that 1) IL-4-accelerated expulsion of T. spiralis, but not expulsion of N. brasiliensis, requires the participation of T cells and mast cells (1, 4); 2) Stat6-deficient mice make normal cytokine responses to primary infection with N. brasiliensis (1), but decreased IL-4, decreased IL-3 and increased IFN-{gamma} responses to infection with T. spiralis; 3) intestinal MMC responses and mast cell degranulation are considerably increased in Stat6-deficient mice infected with N. brasiliensis (1), but considerably decreased in Stat6-deficient mice infected with T. spiralis; and 4) treatment of Stat6-deficient mice with exogenous IL-4 enhances the expulsion of T. spiralis, but not the expulsion of N. brasiliensis (1).

These observations are compatible with the view that characteristics that may be common to T. spiralis and N. brasiliensis induce T cell production of cytokines that bind to receptors that contain IL-4R{alpha} and activate Stat6. This common step is required for protective immunity against both parasites but promotes host protection against T. spiralis and N. brasiliensis through completely different mechanisms. Direct effects of activated Stat6 on the gut, although still poorly characterized, appear to be necessary and sufficient to expel N. brasiliensis but are not sufficient to expel T. spiralis. Instead, Stat6 signaling appears to promote T. spiralis expulsion primarily through a less direct effect, enhancement of IL-3 and IL-4 production and suppression of IFN-{gamma} production, which, in turn, enhance the intestinal mast cell response required for T. spiralis expulsion. Thus, although Stat6 signaling has a direct inhibitory effect on IL-4-induction of intestinal mastocytosis (1), this negative effect on mastocytosis is outweighed in T. spiralis-infected mice by Stat6 promotion of type 2 cytokine production and inhibition of type 1 cytokine production. In contrast, in mice infected with N. brasiliensis, in which the type 2 cytokine response is Stat6 independent, the inhibitory effect of Stat6 signaling on intestinal mastocytosis and mast cell degranulation predominates (1).

This explanation raises the issue of why type 2 cytokine responses are Stat6 dependent in T. spiralis-infected mice but Stat6 independent in N. brasiliensis-infected mice. It is noteworthy that N. brasiliensis stimulates an almost pure type 2 cytokine response while T. spiralis induces production of considerable IFN-{gamma}, in addition to IL-4. Stat6 signaling may be required more during a primary response to allow type 2 cytokine responses to progress in the presence of cytokines, such as IL-12, IFN-{alpha}ß, or IFN-{gamma}, that can inhibit type 2 responses (37, 38, 39) than to promote the initial production of type 2 cytokines by naive T cells. If so, the mixed nature of the cytokine response to T. spiralis might make its type 2 cytokine component Stat6 dependent. Although plausible, this explanation raises the additional question of why T. spiralis induces a mixed cytokine response while N. brasiliensis induces an almost pure type 2 response.

In this regard, it has been observed that gastrointestinal nematodes such as T. spiralis and Trichuris muris, which live within cells, induce considerably more IFN-{gamma} production than gastrointestinal nematodes that have an entirely extracellular existence, such as N. brasiliensis, H. polygyrus, and S. venezuelensis (3). Perhaps the presence of parasites within host cells evolved as a trigger of IFN-{gamma} production because IFN-{gamma} is required for host defense against many intracellular parasites (40, 41, 42, 43, 44, 45, 46, 47, 48, 49). Alternately, stimuli associated with N. brasiliensis, but not T. spiralis, may inhibit production of IFN-{gamma}, perhaps by suppressing the production of IL-12 or IFN-{alpha}ß by dendritic cells and macrophages. Experiments that examine the Stat6 dependence of type 2 cytokine responses, intestinal mastocytosis, and T. spiralis expulsion in mice infected simultaneously with T. spiralis and N. brasiliensis may allow differentiation of these two possibilities by determining whether the T. spiralis-associated Stat6 dependence or the N. brasiliensis-associated Stat6 independence dominates.


   Acknowledgments
 
We thank Dr. Richard Grencis for his thoughtful comments and his gift of anti-c-kit mAb and Drs. Richard Locksley, Nancy Noben-Trauth, and James Ihle for their generous gifts of recombinant mice.


   Footnotes
 
1 This work was supported in part by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, United States Department of Agriculture CRIS 1265-32000-049, National Institutes of Health Grants RO1 AI35987-06 and RO1 AI44971-01, and Wellcome Trust Grant 44494.Z.95/Z. Back

2 Address correspondence and reprint requests to Dr. Fred D. Finkelman, Department of Internal Medicine, Research Service (151), Cincinnati Veterans Administration Medical Center, 3200 Vine Street, Cincinnati, OH 45220. E-mail address: Back

3 Abbreviations used in this paper: L1, first-stage larvae; CCCA, Cincinnati cytokine capture assay; MMCP1, mouse mast cell protease 1; MMC, mucosal mast cells; sIL-13R{alpha}2-Fc, soluble IL-13R{alpha}2-Fc; IL-4C, IL-4/anti-IL-4 mAb complex. Back

Received for publication October 14, 1999. Accepted for publication December 6, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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