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The Journal of Immunology, 2004, 172: 4672-4675.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Early IL-4 Production Governs the Requirement for IL-27-WSX-1 Signaling in the Development of Protective Th1 Cytokine Responses following Leishmania major Infection1

David Artis*, Leanne M. Johnson*, Karen Joyce*, Christiaan Saris{dagger}, Alejandro Villarino*, Christopher A. Hunter* and Phillip Scott2,*

* Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104; and {dagger} Department of Inflammation Research, Amgen, Inc., Thousand Oaks, CA 91320


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
There are conflicting reports on the requirements for the IL-27-WSX-1 pathway in the development of Th type 1 responses and resistance to intracellular pathogens; although early IFN-{gamma} production and resistance to Leishmania major are impaired in the absence of WSX-1 signaling, WSX-1−/− mice generate robust IFN-{gamma} responses and control infection with other intracellular protozoan pathogens. In this report, we resolve these conflicting observations and demonstrate that, in the absence of IL-4, WSX-1 is not required for early IFN-{gamma} production and control of L. major. Thus, the requirement for WSX-1 signaling in Th type 1 cell differentiation is restricted to conditions in which IL-4 is produced.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Control of intracellular pathogens is critically dependent on the differentiation of naive CD4+ T cells into effector Th type 1 (Th1)3 cells. A complex network of intracellular signaling events program CD4+ T cells for IFN-{gamma} production, including expression of T-bet, remodeling of the IFN-{gamma} gene, and expression of IL-12R{beta}2 (1). Recent studies demonstrated that the class I cytokine receptor WSX-1 has structural and functional homology to the IL-6/IL-12 receptor family (2, 3, 4). The ligand for WSX-1 is IL-27, a heterodimeric cytokine composed of EBI3 (an IL-12p40-related protein) and p28 (an IL-12p35-related protein) (5). The similarities between IL-12/IL-12R and IL-27/WSX-1 predicted a role for the latter pathway in the differentiation of CD4+ Th1 cells. Supporting this hypothesis, WSX-1 signaling induces STAT-1-dependent expression of T-bet and primes naive CD4+ T cells for IL-12-dependent IFN-{gamma} production (5, 6), whereas WSX-1−/− mice have defects in IFN-{gamma} production (3, 4).

However, the requirement for WSX-1 in Th1 cell development is controversial. For instance, WSX-1−/− mice are more susceptible to Listeria monocytogenes and Leishmania major, two pathogens that are controlled by Th1 cytokine responses (3, 4). In contrast, we and others (7, 8) have demonstrated that WSX-1−/− mice can generate robust IFN-{gamma} responses following infection with the intracellular pathogens Toxoplasma gondii and Trypanosma cruzi. To investigate the basis for these paradoxical results, we re-examined the role of the WSX-1 pathway in Th1 cell development and immunity to L. major infection. WSX-1−/− mice generated low levels of IFN-{gamma} early, but equivalent Leishmania-specific IFN-{gamma} responses to WT mice later in infection, and, in contrast to published studies, successfully controlled parasite replication and resolved cutaneous lesions. Therefore, susceptibility to leishmaniasis in WSX-1−/− mice was restricted to the early stages of this infection, coincident with the production of Leishmania-specific IL-4. Furthermore, administration of anti-IL-4 mAb in the first 4 wk of infection abrogated the requirement for WSX-1 in early IFN-{gamma} production and control of infection, demonstrating that the presence of IL-4 regulates the requirement for WSX-1 in Th1 cell development.


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

WSX-1−/− mice were generated as previously described (4) and provided by Dr. C. Saris (Amgen, Thousand Oaks, CA). Sex- and age-matched wild-type (WT) C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME) were used as controls. In all of the experiments, mice were infected at 5–8 wk of age, and experimental groups contained three to five animals. Experiments followed the guidelines of the University of Pennsylvania Institutional Animal Care and Use Committee.

Parasites and Ag

Two million stationary-phase promastigote L. major parasites (MHOM/IL/80/Friedlin) were injected, and lesion size and parasite numbers were determined as previously described (9). Soluble Leishmania Ag (SLA) was prepared as previously described (10).

In vivo depletions

Neutralizing anti-IL-4 mAb (11B11) (National Cancer Institute Biological Resource Branch, Frederick, MD) was administered at 3–5 mg/dose i.p. every 4 days for the first 4 wk of infection.

Cell culture and cytokine analysis

Lymph node (LN) cells were harvested from L. major-infected mice, and cell suspensions were prepared as previously described (9). In some studies, cells were cultured in the presence of recombinant murine IL-12 (10 ng/ml) (a gift from Drs. S. Wolf and J. Sypek (Wyeth, Cambridge, MA)). For in vitro assays, spleen and LN cells were isolated from naive animals, labeled with CFSE (1.25 µM; Molecular Probes, Eugene, OR), and stimulated for 4 days with soluble anti-CD3 mAb and anti-CD28 mAb (both 1 µg/ml) in the presence or absence recombinant murine IL-12 (10 ng/ml) or anti-IL-4 mAb (11B11; 10 µg/ml). Cytokine production was assayed as previously described (9).

Determination of parasite-specific IgG1

Parasite-specific IgG1 responses were determined by capture ELISA as previously described (11).

Statistical analysis

Significant differences (p < 0.05) between experimental groups were determined using the Mann-Whitney U test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
WSX-1−/− signaling is not required for Leishmania-specific IFN-{gamma} responses and efficient control of parasite replication

To examine the role of WSX-1 in immunity to L. major, WT and WSX-1−/− mice were infected with L. major, and infection was monitored. Consistent with the results of Yoshida et al. (4), WSX-1−/− mice exhibited enhanced susceptibility to infection compared with WT mice, developing significantly larger lesions and higher parasite burdens in the first 6 wk postinfection (Fig. 1). Surprisingly, later in infection, WSX-1−/− mice resolved their cutaneous lesions (Fig. 1A) and controlled parasite replication (B), demonstrating that the protective role WSX-1 plays following L. major infection is transient.



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  		FIGURE 1. WSX-1−/− mice can control L. major infection and resolve cutaneous lesions. WT and WSX-1−/− mice were infected with 2 x 106 L. major promastigotes in the hind footpad. Lesion size was determined by measuring swelling of the infected footpad and subtracting that of the uninfected contralateral footpad (A), and parasite load in the footpad was quantified by limiting dilution analysis at various times postinfection (B). Values represent the mean ± SD for three to five mice per group and are representative of three experiments. *, Significant difference between WT and WSX-1−/− mice (p < 0.05).

 
In parasite-specific recall responses, LN cells from infected WT and WSX-1−/− mice produced little or no IFN-{gamma} 4 days after infection (Fig. 2A) but substantial levels of IL-4 (B), consistent with previous studies (12). However, although WT mice down-regulated this IL-4 response, levels of Leishmania-specific IL-4 were maintained for at least 2 wk in infected WSX-1−/− mice (Fig. 2, A and B). These results suggest that WSX-1 promotes Leishmania-specific Th1 cytokine responses early following infection. By 6 wk postinfection, IL-4 levels decreased in infected WSX-1−/− mice (Fig. 2B), and equivalent levels of Ag-specific IFN-{gamma} production were observed in WT and WSX-1−/− mice (A). Furthermore, there was a similar frequency of CD4+ T cells producing IFN-{gamma} at 27 wk postinfection (Fig. 2, C and D). The emergence of Leishmania-specific Th1 responses in infected WSX-1−/− mice was consistent with their ability to control infection and resolve their lesions (Fig. 1). Therefore, the requirement for WSX-1 in Th1 cell differentiation and immunity to L. major was restricted to early stages of infection when IL-4 responses are observed.



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  		FIGURE 2. Defective Leishmania-specific IFN-{gamma} responses in WSX-1−/− mice are associated with IL-4 production. WT and WSX-1−/− mice were infected with 2 x 106 L. major promastigotes in the hind footpad. At various times postinfection, draining LN cells were isolated and cultured in medium alone (med) or with SLA for 72 h. Secretion of IFN-{gamma} (A) and IL-4 (B) was determined by ELISA. The frequency of SLA-stimulated WT (C) and WSX-1−/− (D) CD4+ T cells producing IFN-{gamma} was determined at wk 27 postinfection by intracellular cytokine staining. Values represent the mean of pooled (day 4) or individual LN ± SD for three to five mice per group and are representative of three experiments. *, Significant difference between WT and WSX-1−/− mice (p < 0.05).

 
Anti-IL-4 mAb treatment partially recovers IL-12 responsiveness and Th1 cell differentiation in naive WSX-1−/− CD4+ T cells

These studies suggest that WSX-1 may not be required for IFN-{gamma} production in the absence of IL-4. To directly test this, naive WT and WSX-1−/− lymphocytes were isolated and stimulated with anti-CD3/anti-CD28 in the presence of control or anti-IL-4 mAb. Under neutral conditions, the frequency of WT and WSX-1−/− IFN-{gamma}+CD4+ T cells was similar, and addition of anti-IL-4 mAb did not significantly affect the percentage of IFN-{gamma}-producing cells (data not shown). In contrast, under Th1 conditions, the frequency of WSX-1−/− CD4+ T cells producing IFN-{gamma} was lower than that observed in WT cultures (Fig. 3, control). However, blockade of IL-4 resulted in a 47% increase in the frequency of WSX-1−/− CD4+ T cells producing IFN-{gamma} compared with control-treated cultures (Fig. 3), although the frequency of IFN-{gamma}-positive WSX-1−/− CD4+ T cells was still lower than that observed in WT cultures. The incomplete recovery in IFN-{gamma} production in WSX-1−/− CD4+ T cells may be the result of insufficient IL-27 production in these culture conditions or incomplete blockade of IL-4. Nevertheless, blockade of IL-4 clearly resulted in increased WSX-1−/− CD4+ Th1 cell differentiation.



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  		FIGURE 3. Anti-IL-4 mAb treatment partially recovers IL-12 responsiveness and Th1 cell differentiation in naive WSX-1−/− CD4+ T cells. Spleen and LN cells were isolated from naive WT and WSX-1−/− mice, labeled with CFSE, and cultured for 4 days with anti-CD3 mAb, anti-CD28 mAb, and rIL-12 in the presence of control or anti-IL-4 mAb. Cells were stained for surface CD4 and intracellular IFN-{gamma}. CD4+ T cell proliferation and IFN-{gamma} production were analyzed by flow cytometry. Numbers represent the frequency of proliferating CD4+ T cells staining positive for IFN-{gamma}. Results are representative of three individual experiments.

 
Anti-IL-4 mAb-treated WSX-1−/− mice develop Leishmania-specific Th1 responses and control parasite replication following L. major infection

Based on our in vitro findings, we hypothesized that in the absence of IL-4 WSX-1 would not be required for Th1 cell differentiation and immunity to L. major. To test this, L. major-infected WSX-1−/− mice were treated with anti-IL-4 mAb for the first 4 wk of infection, which substantially reduced IL-4 production in these mice (data not shown). This treatment did not significantly enhance IFN-{gamma} production in WT LN cultures (data not shown). In contrast, LN cells isolated from anti-IL-4 mAb-treated WSX-1−/− mice secreted significantly higher levels of IFN-{gamma} compared with untreated WSX-1−/− controls and exhibited enhanced IL-12 responsiveness (Fig. 4A). Moreover, blockade of IL-4 significantly enhanced the frequency of IFN-{gamma}-producing CD4+ T cells (Fig. 4B) and reduced Leishmania-specific serum IgG1 responses in infected WSX-1−/− mice (C). The expression of WSX-1-independent Th1 responses in the absence of IL-4 (Fig. 4, A and B) was reflected in the ability of anti-IL-4 mAb-treated WSX-1−/− mice to resolve lesions (D) and control parasite replication (E). Taken together, these studies demonstrate that, in the absence of IL-4, WSX-1 is not required for the development of protective Th1 cytokine responses or control of L. major infection.



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  		FIGURE 4. Anti-IL-4 mAb treatment recovers Leishmania-specific Th1 responses and resistance to L. major in WSX-1−/− mice. WT and WSX-1−/− mice were infected with 2 x 106 L. major promastigotes in the hind footpad and treated with control or anti-IL-4 mAb for the first 4 wk of infection. At day 18 postinfection, LN cells were isolated and cultured in medium alone (med) or SLA (with or without rIL-12) for 72 h. IFN-{gamma} secretion and the frequency of cytokine-positive CD4+ T cells were analyzed by ELISA (A) and intracellular cytokine staining (B). Numbers represent the percentage of CD4+ T cells secreting IFN-{gamma} following stimulation in the presence of rIL-12. Lesion size was determined by measuring swelling of the infected footpad and subtracting that of the uninfected contralateral footpad (D). Serum Leishmania-specific IgG1 responses (C) and parasite load in the footpad (E) were determined at wk 6 postinfection. Values represent the mean ± SD for three to five mice per group and are representative of three experiments. *, Significant difference between untreated and anti-IL-4 mAb-treated WSX-1−/− mice (p < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this report, we demonstrate that the requirement for WSX-1 in Th1 cell differentiation is restricted to a cytokine milieu in which IL-4 is present; following blockade of IL-4, or at later stages of L. major infection when IL-4 responses have waned, WSX-1−/− mice develop potent IFN-{gamma} responses and resolve lesions. Recent studies demonstrated that, in addition to IFN-{gamma}R signaling, IL-27-WSX-1 signaling induces STAT-1-dependent expression of T-bet (6). T-bet is a critical transcription factor that promotes Th1 cell development (1, 13, 14, 15, 16). During an immune response characterized by mixed Th1/Th2 cytokine responses (e.g., following L. major infection), optimal induction of Th1 cell differentiation may require combined IFN-{gamma}- and IL-27-induced T-bet expression to optimally promote IFN-{gamma} transcription, induce expression of IL-12R{beta}2, and inhibit IL-4-induced GATA-3 expression. Supporting this, a recent in vitro study demonstrated that, although IL-27 is not sufficient to drive Th1 cell differentiation, it can suppress GATA-3 expression and promote T-bet induction via STAT1-dependent and -independent mechanisms (17). Based on our results, we propose that in the absence of IL-4-induced GATA-3 expression WSX-1 is dispensable for optimal Th1 cell differentiation.

A conditional role for WSX-1 in Th1 cell differentiation is supported by a number of observations. First, the requirement for WSX-1 in the development of Th1 cytokine responses following L. major infection was restricted to early in infection when significant levels of IL-4 are produced. Second, blockade of IL-4 completely recovered IFN-{gamma} production and host defense in infected WSX-1−/− mice. Similarly, anti-IL-4 mAb treatment of WSX-1−/− mice infected with T. cruzi led to increased parasite control, although IFN-{gamma} production in anti-IL-4 mAb-treated mice was not assessed (8). Lastly, the frequency of naive WSX-1−/− CD4+ T cells secreting IFN-{gamma} following polyclonal stimulation was also significantly higher following anti-IL-4 mAb treatment. Taken together, these studies suggest that WSX-1-dependent promotion of IFN-{gamma} production is restricted to a mixed Th1/Th2 cytokine environment.

These results provide an explanation for conflicting reports on the role of IL-27-WSX-1 signaling in Th1 cytokine-dependent immunity to intracellular pathogens. Thus, following infection of B6 mice with L. major in which significant IL-4 responses are induced, WSX-1 expression is essential in the early promotion of IFN-{gamma} production. In contrast, following exposure to pathogens such as T. gondii or T. cruzi that induce rapid and robust NK and CD4+ T cell-dependent IFN-{gamma} responses in the absence of significant amounts of IL-4, WSX-1 signaling is not necessary for IFN-{gamma} production and host defense (7, 8, 18). In fact, fatal infection-induced inflammatory responses develop in these model systems (7, 8). In summary, this report demonstrates that WSX-1-dependent induction of IFN-{gamma} is restricted to a nonpolarized cytokine environment in which IL-4 is present.


   Acknowledgments
 
We thank members of the Department of Pathobiology for useful discussions.


   Footnotes
 
1 This work was supported by grants from The Wellcome Trust (059967/B/99/Z) (to D.A.), State of Pennsylvania (to C.A.H.), and National Institutes of Health (AI.42332 (to C.A.H.) and AI.35914 (to P.S.)). A.V. is a recipient of a Minority Supplement. Back

2 Address correspondence and reprint requests to Dr. Phillip Scott, Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104. E-mail address: pscott{at}vet.upenn.edu Back

3 Abbreviations used in this paper: Th1, Th type 1; WT, wild type; SLA, soluble Leishmania Ag; LN, lymph node. Back

Received for publication December 23, 2003. Accepted for publication February 24, 2004.


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