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Cutting Edge: IL-4 Receptor Expression by Non-Bone Marrow-Derived Cells Is Required to Expel Gastrointestinal Nematode Parasites¹

Joseph F. Urban, Jr.^2,*, Nancy Noben-Trauth, Lisa Schopf^*, Kathleen B. Madden and Fred D. Finkelman^3,,¶

^* U.S. Department of Agriculture, Agricultural Research Service, Animal and Natural Resources Institute, Immunology and Disease Resistance Laboratory, Beltsville, MD 20705; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814; Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; Division of Immunology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and ^¶ Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220

	Abstract

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Expulsion of two gastrointestinal nematode parasites, Nippostrongylus brasiliensis and Trichinella spiralis, is similar in that both require IL-4R expression, but different in that T cells and mast cells are required for IL-4-induced expulsion of T. spiralis but not N. brasiliensis. To examine the role of IL-4R signaling in immunity to these parasites, we studied worm expulsion in chimeric mice that selectively expressed IL-4R on bone marrow-derived or non-bone marrow-derived cells. N. brasiliensis was expelled by mice that expressed IL-4R only on non-bone marrow-derived cells, but not by mice that expressed IL-4R only on bone marrow-derived cells. Although T. spiralis expulsion required IL-4R expression by both bone marrow- and non-bone marrow-derived cells, IL-4 stimulation eliminated the requirement for IL-4R expression by bone marrow-derived cells. Thus, direct IL-4R signaling of nonimmune gastrointestinal cells may be generally required to induce worm expulsion, even when mast cell and T cell responses are also required.

	Introduction

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Type 2 cytokines, particularly IL-4 and IL-13, are critical for host defense against nematode parasites, especially those that reside in the gut (1, 2, 3). However, the mechanisms by which these cytokines protect against gastrointestinal nematode parasites have not been elucidated and appear to be parasite specific. For example, while IL-4R-mediated Stat6 signaling is required to expel both Nippostrongylus brasiliensis and Trichinella spiralis (4, 5), Stat6 signaling has different roles in the expulsion of each worm. Stat6 signaling is not required for a Th2 response and actually limits intestinal mastocytosis in mice infected with N. brasiliensis, but is required during the effector stage of worm expulsion, which is mast cell independent (4). In contrast, Stat6 signaling is required in mice infected with T. spiralis to induce the type 2 cytokine response and the cytokine-dependent mast cell response that are required to expel this parasite (5).

These observations and considerations suggested to us that different cell types would need to respond to IL-4 and IL-13 to expel N. brasiliensis and T. spiralis. IL-4R signaling of non-bone marrow-derived cells, such as intestinal epithelium, goblet cells, and smooth muscle, might be important to induce changes in intestinal physiology that could expel N. brasiliensis, while IL-4R signaling of T cells and mast cells might be required to induce the mast cell response needed to expel T. spiralis. To test this hypothesis, we evaluated the abilities of chimeric mice that express IL-4R solely on bone marrow-derived or non-bone marrow-derived cells to expel these two parasites. As hypothesized, we found that IL-4R expression by bone marrow-derived cells is required for T. spiralis but not N. brasiliensis expulsion. However, surprisingly, T. spiralis expulsion, like N. brasiliensis expulsion, requires IL-4R expression on non-bone marrow-derived cells, even though mice that selectively lack IL-4R expression on these cells make larger than normal mast cell responses.

	Materials and Methods

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Mice

Female BALB/c wild-type and RAG2-deficient mice were purchased from Taconic Farms (Germantown, NY). BALB/c IL-4R-deficient mice (6), which cannot respond to either IL-4 or IL-13 (3), and BALB/c mice deficient in both IL-4R and RAG2 were bred at the National Institutes of Health (Bethesda, MD). CB17 SCID mice and strain-matched normal controls and athymic nude mice were purchased through the National Cancer Institute (Bethesda, MD). Mice were used at 8–12 wk of age.

Parasites

Methods for maintaining N. brasiliensis and T. spiralis, for s.c. inoculation with N. brasiliensis third-stage larvae and oral inoculation with T. spiralis muscle larvae, and for evaluating numbers of adult worms in the intestines of infected mice have been described (4, 5).

Production of chimeric mice

PBS, injected through an 18-gauge needle, was used to flush bone marrow cells from the femurs and tibias of wild-type and IL-4R-deficient donor mice. Cells were washed once and resuspended in PBS. Recipient RAG2-deficient and RAG2/IL-4R-double-deficient mice were irradiated with 800 rad, then injected i.v. with 40 x 10⁶ bone marrow cells in 0.2 ml of PBS. Phenotypes of mice generated in this manner are shown in Table I. Bone marrow-chimeric mice were tested 4–6 wk after reconstitution for expression of CD3 and B220 on PBMCs. All mice were maintained on antibiotic water (trimethoprim-sulfa) for 4–6 wk after reconstitution and before worm inoculation.

View this table: [in this window] [in a new window]   Table I. Chimeric mice used to test the role of IL-4R in worm expulsion

ACK-2, a blocking anti-c-kit mAb, (7) obtained from Dr. R. Grencis (University of Manchester, Manchester, U.K.), was grown as ascites in Pristane-primed athymic nude mice and purified by ammonium sulfate precipitation and DEAE-cellulose chromatography.

Long-acting IL-4

Complexes of IL-4 and an anti-IL-4 mAb (11B11) (8) at a 2:1 molar ratio (1:5 weight ratio) were prepared by mixing recombinant mouse IL-4(PeproTech, Rocky Hill, NJ) and 11B11 (Verax, Lebanon, NH) at this ratio in a 1.5-ml Eppendorf tube for 3 min, then diluting the solution with saline to a concentration of 50 µg of IL-4 and 250 µg of 11B11 per ml. When indicated, mice were injected with 0.2 ml of this solution i.v. Previous studies demonstrate that these complexes maintain an elevated level of serum IL-4 for 3–5 days by slowly dissociating in vivo (9). Because complexes never contain more than one molecule of IgG, they neither fix complement nor associate with low-affinity FcR. Because 11B11 neutralizes IL-4, intact complexes have no ability to interact with IL-4 receptors; only IL-4 released by complex dissociation can trigger these receptors.

Measurement of IL-4 and IFN- production

In vivo cytokine production was measured by the Cincinnati cytokine capture assay (CCCA)⁴ (10). Mice were injected i.v. with 10 µg of biotin-labeled anti-IL-4 mAb (BVD4-1D11) (11) and 10 µg of biotin-labeled anti-IFN- mAb (R46A2) (12). These mAbs bind secreted IL-4 or IFN-, respectively, and decrease their use, excretion, and catabolism; however, cytokine neutralization is not sufficiently complete to suppress cytokine-dependent immune function. Complexes of biotin-anti-IL-4 mAb with IL-4 or biotin-anti-IFN- mAb with IFN- were detected by ELISA (10).

Determination of intestinal mucosal mast cell number and serum MMCP1 levels

Intestinal mucosal mast cells were counted in Swiss rolls made from segments of jejunum (13). An ELISA kit purchased from Moredun Scientific (Penicuik, Scotland) was used to quantitate serum levels of mouse mast cell protease 1 (MMCP1), a mast cell-released protease that has a long serum half-life and can be used as an index of mast cell degranulation (14).

Determination of serum IgE levels

Serum IgE levels were determined by ELISA (4).

Determination of peripheral blood B and T cells

Heparinized blood samples were obtained from irradiated and reconstituted mice, treated with erythrocyte lysing buffer, then washed, stained with FITC-labeled mAbs specific for the B cell marker, B220 (mAb 6B2), or the T cell marker, CD3 (2C11), and analyzed by flow cytometry.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
IL-4 induces N. brasiliensis expulsion in the absence of B, T, and mast cells

Previous studies have demonstrated that T cell-deficient mice fail to spontaneously expel either N. brasiliensis or T. spiralis (2), that mast cell-deficient mice spontaneously expel N. brasiliensis but not T. spiralis (14, 15), and that treatment with exogenous IL-4 causes T cell-deficient mice to expel N. brasiliensis (16) but fails to induce T. spiralis expulsion by mice deficient in either T cells or mast cells (5). To determine whether IL-4 can induce N. brasiliensis expulsion by mice that lack T cells, B cells, and mast cells, SCID mice were injected with an anti-c-kit mAb that blocks mast cell induction, then inoculated with N. brasiliensis and treated with IL-4. IL-4 treatment effectively induced N. brasiliensis expulsion (Fig. 1).

View larger version (35K): [in this window] [in a new window]   FIGURE 1. IL-4 induces N. brasiliensis expulsion in mice deficient in B, T, and mast cells. CB17 SCID mice (five per group) were inoculated s.c. with 500 N. brasiliensis third-stage larvae and were injected i.p. with 0.5 mg of anti-c-kit mAb or an isotype-matched control mAb 4, 7, and 10 days after worm inoculation. On days 5, 8, and 11 after inoculation, mice were injected i.v. with saline or with IL-4C that contained 10 µg of mouse IL-4 and 50 µg of anti-IL-4 mAb (11B11). Mice were sacrificed 14 days after the initiation of IL-4 treatment and numbers of adult worms per mouse, eggs per female worm, and intestinal mucosal mast cells were determined. Means and SE are shown in this and in subsequent figures. Similar results were observed in a second experiment.

These results suggested that IL-4 promotes N. brasiliensis expulsion by acting on cells that are not generally associated with immune function, such as intestinal epithelial or smooth muscle cells. To rule out the possibility that any bone marrow-derived cells must respond to IL-4/IL-13 to induce N. brasiliensis expulsion, chimeric mice were produced (Table I) that selectively lacked IL-4R on bone marrow-derived or on non-bone marrow-derived cells, that had IL-4R on both cell types (positive control), or that lacked B cells and T cells and also lacked IL-4R on non-bone marrow-derived cells (negative control). With the exception of the last group, chimeric mice had normal percentages of B and T cells in peripheral blood (Fig. 2, top panel). Mice that expressed IL-4R only on bone marrow-derived cells made a strong IgE response to N. brasiliensis infection (Fig. 2, second panel) and generated considerably larger IL-4 responses without generating larger IFN- responses than other mice in this experiment (Fig. 2, third panel), but failed to expel N. brasiliensis, even when treated with sufficient IL-13 to expel this parasite from SCID mice (Fig. 2, fourth and fifth panels, and data not shown). In contrast, mice that expressed IL-4R only on non-bone marrow-derived cells expelled N. brasiliensis spontaneously, even though they failed to secrete IgE and made IL-4 and IFN- responses that were, respectively, smaller and similar to those made by mice that expressed IL-4R only on bone marrow cells.

View larger version (34K): [in this window] [in a new window]   FIGURE 2. IL-4R expression on non-bone marrow-derived cells allows mice to expel N. brasiliensis. In a single experiment, RAG2-deficient or RAG2/IL-4R-double-deficient mice were irradiated and reconstituted with spleen cells from wild type mice, RAG2-deficient mice, or IL-4R-deficient mice to produce mice that expressed IL-4R on both bone marrow-derived and non-bone marrow-derived cells (Wild-type; used as a positive control), only on non-bone marrow-derived cells (IL-4R-/- BM), only on bone marrow-derived cells (IL-4R-/- non-BM), and, as a negative control, mice that lacked B and T cells and did not express IL-4R on non-bone marrow-derived cells (No B or T Cells). Percentages of B and T cells in peripheral blood were determined 9 wk after reconstitution. Twelve weeks after reconstitution, mice were inoculated s.c. with 500 third-stage N. brasiliensis larvae. Serum IgE levels were determined by ELISA 7 and 12 days after worm inoculation and IL-4 and IFN- production were determined by CCCA 12 days after inoculation. One set of mice was sacrificed 17 days after worm inoculation and numbers of adult worms per mouse and eggs per female worm were determined. A second set of mice was treated i.p. with 10 µg of recombinant mouse IL-13 per day for 6 days, starting 15 days after worm inoculation. Mice were sacrificed 1 day after the last IL-13 treatment and numbers of adult worms per mouse and eggs per female worm were determined.

IL-4R must be expressed on both bone marrow-derived cells and non-bone marrow-derived cells to expel T. spiralis

The mast cell and T cell dependence of T. spiralis expulsion, even in IL-4-treated mice (5), suggested that the pattern of IL-4 responsiveness necessary for expulsion of this parasite would be opposite to that required for N. brasiliensis expulsion. IL-4 responsiveness by bone marrow-derived cells, rather than non-bone marrow-derived cells, would be both necessary and sufficient for T. spiralis expulsion. However, although T. spiralis-infected mice that expressed IL-4R only on bone marrow-derived cells generated IL-4 and MMCP1 responses that were substantially greater than those made by wild-type mice, they failed to resolve infection, even when treated with IL-4C (Fig. 3). T. spiralis-infected mice differed from N. brasiliensis-infected mice by also requiring IL-4R-responsive bone marrow-derived cells to expel intestinal worms, possibly because IL-4 responses were considerably decreased and IFN- responses considerably increased in T. spiralis-infected mice that lacked IL-4R expression on these cells. In support of this possibility, IL-4 treatment induced mice that selectively lacked IL-4R expression on bone marrow-derived cells to expel T. spiralis.

View larger version (35K): [in this window] [in a new window]   FIGURE 3. IL-4R must be expressed on both bone marrow-derived cells and non-bone marrow-derived cells to expel T. spiralis. Mice chimeric for IL-4R were generated as described in Fig. 2. In one experiment, an additional group (IL-4R-/-) was generated by reconstituting irradiated RAG2/IL-4R-double-deficient mice with bone marrow cells from IL-4R-deficient mice. Six weeks after reconstitution, mice were inoculated orally with 50 T. spiralis first-stage muscle larvae. IL-4 and IFN- production were determined by CCCA and serum MMCP1 levels were determined by ELISA 14 days after worm inoculation. One set of mice was sacrificed 14 days after worm inoculation and numbers of adult worms per mouse were determined. A second set of mice was treated with IL-4C (10 µg of mouse IL-4 plus 50 µg of 11B11) every 3 days for 11 days, starting 15 days after worm inoculation. Mice were sacrificed 2 days after the last IL-4C treatment and numbers of adult worms per mouse were determined. Similar results were observed in a second experiment.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

A different and more complex situation exists in mice infected with T. spiralis. Both bone marrow-derived cells and non-bone marrow-derived cells must express IL-4R for mice to spontaneously expel this parasite. However, although bone marrow-derived T cells and mast cells must be present to expel T. spiralis, even when mice are treated with pharmacologic doses of IL-4 (5), these cells do not have to be IL-4/IL-13-responsive to contribute to IL-4-induced expulsion (Fig. 3). In accord with this observation, T. spiralis expulsion is normal or near-normal in IL-4-deficient mice, which still produce IL-13 (5). Neither T cells nor mast cells in IL-4-deficient mice can be signaled through IL-4R because neither cell type responds to IL-13 (3, 17). It remains unclear why IL-4-deficient mice have near normal ability to expel T. spiralis while mice that lack IL-4R on bone marrow-derived cells require treatment with exogenous IL-4 to expel this parasite. Possibly, IL-13 acts on bone marrow-derived cells other than mast cells or T cells, such as dendritic cells or macrophages, to inhibit production of IL-12, which suppresses mastocytosis (18, 19).

Our observations raise questions about how IL-4R signaling 1) works independently of T cells and mast cells to expel N. brasiliensis, and 2) acts together with IL-4-unresponsive T cells and mast cells to expel T. spiralis. Because adult forms of both worms reside in the small intestine, IL-4/IL-13 probably promote expulsion through effects at this site. In this regard, in vivo treatment of mice with IL-4 and/or IL-13 increases longitudinal smooth muscle contractility in the small intestine, intestinal epithelial permeability, and intestinal secretory responses to PG E₂, and mucus secretion, while inhibiting the stimulatory effect of glucose on intestinal absorption (2, 20, 21). Any or all of these effects, which are also induced by gastrointestinal worm infection through an IL-4R-mediated process, may contribute to N. brasiliensis expulsion by modifying the worm’s ability to maintain contact with jejunal mucosa.

For T. spiralis, the challenge is to understand how IL-4/IL-13-unresponsive T cells and mast cells act together with IL-4/IL-13-responsive intestinal cells to induce worm expulsion. Because IL-4 treatment fails to induce a mast cell response or worm expulsion in T cell-deficient, T. spiralis-infected mice (5), while it induces worm expulsion in mice that selectively express IL-4R on non-bone marrow-derived cells (Fig. 3), we hypothesize that T cells contribute to T. spiralis expulsion through two mechanisms: 1) they promote mastocytosis and mast cell degranulation through an IL-4R-independent mechanism, such as IL-3 secretion (13); and 2) they secrete IL-4 and IL-13, which directly stimulate intestinal cells. These mechanisms may be synergistic because IL-4 and IL-13 rapidly increase the responsiveness of mice to mast cell-produced mediators, such as histamine (22). Consistent with this hypothesis, T. spiralis-infected mice have been shown to have increased sensitivity to histamine (23) that is IL-4R dependent (R. Strait, J. Urban, and F. Finkelman, unpublished data). Thus, IL-4R signaling may promote T. spiralis expulsion primarily by increasing the sensitivity of intestinal cells to mediators released by activated mast cells.

	Acknowledgments

 
We thank Tatyana Orekhova for her expert technical assistance and Debra Donaldson for her gift of recombinant mouse IL-13.

	Footnotes

 
¹ This work was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, National Institutes of Health Grants RO1 AI35987, RO1 AI44971, and R21 AI46972, U.S. Department of Agriculture CRIS 1265-32000-049, and Uniformed Services University of the Health Sciences Research Protocol RO86CD.

² Current address: U.S. Department of Agriculture, Beltsville Human Nutrition Research Center, Beltsville, MD 20705.

³ Address correspondence and reprint requests to Dr. Fred D. Finkelman, Cincinnati Veterans Administration Medical Center, Research Service (151), 3200 Vine Street, Cincinnati, OH 45220. E-mail address: ffinkelman{at}mem.po.com

⁴ Abbreviations used in this paper: CCCA, Cincinnati cytokine capture assay; MMCP1, mouse mast cell protease 1.

Received for publication September 18, 2001. Accepted for publication October 3, 2001.

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Top Abstract Introduction Materials and Methods Results Discussion References

 

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				M. Rodriguez-Sosa, J. R. David, R. Bojalil, A. R. Satoskar, and L. I. Terrazas Cutting Edge: Susceptibility to the Larval Stage of the Helminth Parasite Taenia crassiceps Is Mediated by Th2 Response Induced Via STAT6 Signaling J. Immunol., April 1, 2002; 168(7): 3135 - 3139. [Abstract] [Full Text] [PDF]

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