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Cutting Edge: Dendritic Cells Are Essential for In Vivo IL-12 Production and Development of Resistance against Toxoplasma gondii Infection in Mice

Cheng-Hu Liu^*, Yu-ting Fan^*, Alexandra Dias, Lisia Esper, Radiah A. Corn^*, Andre Bafica^,, Fabiana S. Machado and Julio Aliberti^1,

^* Department of Immunology, Duke University Medical Center, Durham, NC 27710; Division of Molecular Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Laboratorio de Imunobiologia, Instituto Goncalo Moniz, Fundacao Osvaldo Cruz, Salvador, BA, Brazil

	Abstract

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A powerful IFN- response is triggered upon infection with the protozoan parasite, Toxoplasma gondii. Several cell populations, including dendritic cells (DCs), macrophages, and neutrophils, produce IL-12, a key cytokine for IFN- induction. However, it is still unclear which of the above cell populations is its main source. Diphtheria toxin (DT) injection causes transient DC depletion in a transgenic mouse expressing Simian DT receptors under the control of the CD11c promoter, allowing us to investigate the role of DCs in IL-12 production. T. gondii-inoculated DT-treated and control groups were monitored for IL-12 levels and survival. We show in this study that DC depletion abolished IL-12 production and led to mortality. Furthermore, replenishment with wild-type, but not MyD88- or IL-12p35-deficient, DCs rescued IL-12 production, IFN--induction, and resistance to infection in DC-depleted mice. Taken together, the results presented in this study indicate that DCs constitute the major IL-12-producing cell population in vivo during T. gondii infection.

	Introduction

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Cell-mediated immune responses to infection with intracellular pathogens are highly dependent on IFN- production by T and NK cells. Genetic depletion of IFN-, its receptor, or several of the genes induced by activation of its receptor, renders mice completely susceptible to infection with several pathogens, including viruses, bacteria, fungi, and protozoa parasite (1). Similarly, genetic depletion of either of the chains that constitute the heterodimeric cytokine IL-12, its receptor, or any of the central signaling components triggered downstream of this receptor results in complete ablation of cell-mediated immune responses (2). Infections with the protozoan parasite, Toxoplasma gondii, have been very useful in the identification of both the cellular and molecular components that are involved in eliciting IFN--dependent immune responses. Consistent with the complete lack of immunity in IFN--deficient mice, IL-12p40-, IL-12p35- and, STAT4-deficient mice fail to develop protective immune responses and succumb early during acute infection (3, 4, 5, 6), clearly indicating that IL-12 is a central component for the development of protective immunity to infection with T. gondii.

The nature of the stimuli that drive IL-12 production during infection with T. gondii has been extensively studied. Several cell populations, including dendritic cells (DCs),² macrophages, and neutrophils, produce IL-12 in vitro after exposure to T. gondii tachyzoites or T. gondii lysates (7, 8, 9). Stimulation via the TLR 11 and the chemokine receptor CCR5 have been shown to induce IL-12 production by DCs in vitro and in vivo (10, 11). Macrophages and neutrophils have similarly been shown to produce IL-12 in a MyD88-dependent manner (12). Despite the growing body of information on the biology of IL-12, it is not clear which cell population is, in fact, key to the initiation of protective immune responses against infection with T. gondii.

In an in vivo injection model, it has been shown that a population of CD8⁺ splenic DCs produce considerable amounts of IL-12 after exposure to an extract of T. gondii tachyzoites, soluble T. gondii Ag (STAg) (7). These findings strongly suggested that DCs are a major source of IL-12 when in the presence of tachyzoites in vivo. However, using a similar model system it also has been shown that neutrophils secrete IL-12 after in vivo stimulation (13), something that suggests that more than one cell population can produce this cytokine in vivo when in the presence of proteins derived from T. gondii. In this study, we aimed to answer the question of whether DCs are the relevant source of IL-12 in vivo during T. gondii infection and to determine their role in the development of host protective immune responses. To address this, we took advantage of a mouse model in which a transgene encoding the Simian diphtheria toxin receptor (DTR) was inserted under control of the cd11c gene promoter, B6.FVB-Tg (Itgax-DTR/EGFP)57^Lan/J (CD11c/DTR-Tg mice), rendering CD11c⁺ cells susceptible to depletion when exposed to DT (14). The data presented here illustrate that DC depletion abolishes both IL-12 production and resistance to T. gondii infection in mice. Moreover, we show that wild-type (WT) DC transfer into DC-depleted mice, just before T. gondii infection, restored protective IL-12/IFN- production and survival to infection. Taken together, the data presented in this study clearly indicate that DCs are a central population in the initiation of IFN--dependent immune responses against infection with T. gondii.

	Materials and Methods

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Mice

C57BL/6 WT mice were purchased from The Jackson Laboratory. CD11c-DTR-Tg (B6.FVB-Tg (Itgax-DTR/EGFP)57^Lan/J) (14), C57Bl/6 MyD88^–/– and C57Bl/6-Il12a^tm1Jm/J (IL-12p35^–/–) mice were bred in specific pathogen-free conditions at the Duke University Animal Care Facility. Mice used in all experiments were 8–10 wk of age. The study procedures were reviewed and approved by the Duke University Institutional Animal Care and Use Committee.

Infections and in vivo stimulation

In vivo infection with T. gondii was performed as described previously (10). Briefly, 20 brain cysts from chronically T. gondii (ME49 strain) infected mice were inoculated into each mouse via i.p. injection. For in vivo stimulation, each mouse was injected i.p. with 25 µg of STAg, which was prepared as described previously (15).

Cell purification

Splenic low-density (LOD) cells were isolated as described previously (15). Briefly, spleens were digested with Liberase CI solution (400 µg/ml; Roche Biochemicals) in RPMI 1640 medium for 30 min at 37°C. The spleens were then homogenized into single-cell suspension, and the LOD cells were obtained by centrifuging the cell suspension with a dense-BSA gradient. To purify splenic DCs, splenic LOD cell suspension was incubated with anti-CD11c MACS beads (Miltenyi Biotec) for 15 min at 4°C, followed by two cycles of MACS-positive selection. The purified DCs were routinely 70–85% CD11c⁺, as determined by flow cytometry.

Peripheral blood LOD cells were prepared according to the following procedures: 250 µl of peripheral blood was collected from each mouse into an Eppendoff tube containing 20 µl 1,000 IU/ml heparin, mixed with 2 ml 30% BSA (Sigma-Aldrich), and centrifuged at 15,000 x g for 15 min at 4°C. The leukocytes in the interface were harvested and washed once with RPMI 1640 medium before flow cytometry analysis.

DC depletions and cell transfer

For systemic depletion of DCs, mice were injected i.p with 100 ng DT (Sigma-Aldrich). For adoptive transfer, 2 x 10⁶ to 1 x 10⁷ splenic DCs from MyD88^–/–, IL-12p35^–/– or WT mice were administered to each mouse via i.p. injection.

Flow cytometry

Splenic or peripheral blood LOD cells were first incubated with anti-CD16/CD32 for 30 min at 4°C. The cells were then incubated with anti-CD11c (FITC) and anti-CD8 (PerCP) for 30 min. For intracellular detection of IL-12, the cells were first cultured in complete RPMI 1640 medium with GolgiStop (BD Pharmingen) for 4 h at 37°C, and then fixed and permeabilized with Cytofix/Cytoperm (BD Biosciences), followed by anti-IL-12p40/p70 Clone C15.6 (PE) staining. All FACS data were acquired using a FACSCalibur (BD Biosciences) and CellQuest software (BD Biosciences) and analyzed with FlowJo software (Tree Star). All Abs were purchased from BD Biosciences/Pharmingen.

Cytokine measurement

IL-12p40, IL-12p70, and IFN- levels in sera or culture supernatant were measured by ELISA, using commercial kits purchased from BD Biosciences.

Statistical analysis

Experimental data are expressed as mean ± SD. The statistical significance of differences in mean values was determined using Student’s t test. Survival data are presented as a Kaplan-Meier survival curve and analyzed with log-rank test. Differences of at least p < 0.05 are considered to be significant.

	Results

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Depletion of DCs abolishes STAg-induced IL-12 production

In vivo injection of STAg induces IL-12 production by splenic CD8⁺CD11c⁺ DCs (7). This microbial extract injection model has proven very useful in understanding the molecular interactions that precede IL-12 secretion by this Ag-presenting cell population, aiding in the identification of microbe-derived peptides and their respective receptors present on the surface of DCs (10, 11, 12, 15, 16). We took advantage of a DT-induced DC depletion model to address the question whether this cell population is critical for in vivo IL-12 production during infection with T. gondii. To establish that the DT-induced CD11c⁺ cell depletion model would be useful to study the role of DCs in IL-12 production and initiation of protective immunity to T. gondii infection, we first tested whether DT-mediated DC depletion would affect STAg-stimulated IL-12 production. WT or CD11c-DTR-Tg mice were treated with DT. 24 h later, animals received either PBS or STAg. After 6 h, the animals were sacrificed and spontaneous IL-12 production was evaluated (Fig. 1A). As can be seen in Fig. 1B, DT-treatment led to depletion of CD11c⁺ cells in CD11c-DTR-Tg, but not in WT mice. Importantly, neither GR-1⁺ nor F4/80⁺ cells were affected by DT treatment (data not shown). Moreover, IL-12 production after STAg injection was abolished in DC-depleted mice, as evidenced by intracellular IL-12 staining (Fig. 1B), spontaneous IL-12 release in culture supernatants (Fig. 1C) and serum levels of the cytokine 6 h after STAg injection (Fig. 1D). Taken together, these results establish that DT-mediated DC depletion is a valuable tool to dissect the role of this cell population in IL-12 production in vivo. Similarly, peritoneal cavity and peripheral lymph node CD11c⁺ cells were depleted after DT treatment, indicating the systemic effect of this toxin (data not shown).

View larger version (26K): [in this window] [in a new window]   FIGURE 1. Depletion of DCs abolishes STAg-induced IL-12 production. A, WT and CD11c/DTR-Tg mice were i.p. injected with PBS (0.2 ml/mouse) or DT (100 ng/mouse); 24 h later, each mouse was then i.p. injected with PBS (0.2 ml/mouse) STAg (25 µg/mouse). At 6 h after injection, enriched splenic DCs were purified and incubated with GolgiStop for 4 h, then stained and analyzed by FACS for intracellular detection of IL-12 (B). Alternatively, DCs were cultivated in complete RPMI 1640 medium for 18 h, and the IL-12p40 in supernatant was measured by ELISA (C). Sera was collected at the same time point, and IL-12p40 levels were detected by ELISA (D). Data are represented as mean ± SD of triplicate samples. Data shown are representative of at least three independent experiments. *, p < 0.05 between control group and DT-treated group sample.

To determine whether DCs are the relevant in vivo source of IL-12 during infection with T. gondii, we infected DT-treated WT or CD11c-DTR-Tg mice with T. gondii cysts (ME49 strain). Five days after infection, serum samples were collected and assayed for IL-12 levels, and survival thereafter was monitored as indicated (Fig. 2A). The efficiency of DC-depletion was verified in peripheral blood samples before infection and as can be seen in Fig. 2, B and C, while DT-treated WT mice have normal levels of circulating CD11c⁺ cells, DT-treated CD11c-DTR-Tg mice were completely depleted of this cell population. Furthermore, serum levels of IL-12p40 5 days postinfection were significantly lower, compared with that of naive animals (Fig. 2D). These data suggest that in vivo DC depletion abolishes innate IL-12 responses and resistance to T. gondii infection. Indeed, DC-depleted mice succumbed to infection earlier than did intact counterparts (Fig. 2E). Taken together, the data presented above indicate that DCs are an important source of IL-12 and are key mediators of protection against infection.

View larger version (21K): [in this window] [in a new window]   FIGURE 2. High mortality and abolished IL-12 production during acute T. gondii infection in DC-depleted mice. A, Both WT and CD11c-DTR-Tg mice were i.p. injected with 100 ng DT at day –1. Twenty-four hours later, all mice were i.p. injected with T. gondii brain cyst homogenates (20 cysts per mouse; ME49 strain). B, Peripheral blood LOD cells at day 0 were analyzed with FACS. C, The average percentage of CD11c+ cells in LOD cells are shown (Student t test; p < 0.05). D, IL-12p40 levels in sera from WT and CD11c-DTR collected at day 5 postinfection were measured by ELISA. Sera of uninfected (naive) mice were used as negative control. Bars represent mean ± SE of the values obtained from at least three animal samples from each experimental group and negative controls. E, Kaplan-Meier survival curve of infected WT and CD11c-DTR-Tg mice (n = at least 7 animals per group). Log-rank test; p = 0.026. Data shown are representative of at least three independent experiments.

Several other cell populations express CD11c under certain conditions, such as activated NK or CD8 T cells (14, 17). However, the depletion of other CD11c-bearing cells seemed unlikely given the lack of detectable changes in absolute NK, CD8⁺ or CD4⁺ T cell numbers after DT administration in naive mice (data not shown). To provide further evidence that CD11c⁺ DCs are the major IL-12-producing cell population during in vivo infection, we transferred WT or MyD88-deficient DCs into CD11c-DTR-Tg DC-depleted mice followed by infection with T. gondii (Fig. 3A). As shown in Fig. 3, B and C, transfer of WT DCs, but not MyD88-deficient DCs, restored IL-12 production and rescued DC-depleted mice from mortality after infection. We conclude that WT DC transfer can restore a resistant phenotype in DC-depleted mice, indicating that DCs are required for survival and that, in accordance with our previous observations (12), the adaptor molecule MyD88 is essential for DC-mediated resistance to infection. Importantly, DC transfer into non-treated WT or CD11c-DTR-Tg mice did not affect IL-12 responses or resistance to infection (data not shown).

View larger version (17K): [in this window] [in a new window]   FIGURE 3. Adoptive transfer of WT, but not MyD88–/–, splenic DCs rescued DC-depleted mice from mortality after T. gondii infection. A, CD11c-DTR-Tg mice were injected with 100 ng DT at day –1. 6 h after DT injection, each mouse received 107 DCs from either WT or MyD88–/– mice. At day 0, all mice were infected i.p. with 20 T. gondii brain cysts. B, Serum IL-12p40 levels at day 5 were tested by ELISA. Sera from infected WT and DC-depleted CD11c-DTR-Tg mice were used as control. Bars represent mean ± SE of the values obtained from at least three animal samples from each experimental group and control groups. C, Kaplan-Meier survival curve of DC recipient mice (n = 5 animals per group). Log-rank test; p = 0.019. Data shown are representative of at least three independent experiments.

To formally establish the role of DC-derived IL-12 production in the development of Th1 cytokine profile and resistance to T. gondii infection, we performed WT or IL-12p35-deficient DC transfers into DC-depleted CD11c-DTR-Tg mice, followed by infection with T. gondii. In agreement with the results presented above, the transfer of WT DC into DC-depleted CD11c-DTR-Tg mice restored serum levels IL-12 as detected 5 days after T. gondii infection (Fig. 4A). In contrast, DC-depleted mice that received IL-12p35-deficient DCs, despite comparable levels of IL-12p40 (data not shown), these animals failed to produce detectable levels of serum IL-12p70 at the same time point. The deficiency of IL-12 production was reflected in a significant reduction in serum IFN- levels 7 days postinfection (Fig. 4B), while DC-depleted mice that received WT DC presented with IFN- levels similar to that of WT controls (Fig. 4B). Finally, the defects in generating protective IFN- responses by IL-12p35-deficient DCs caused high mortality in recipient DC-depleted mice (Fig. 4C), in contrast with DC-depleted mice that received WT DC survived infection (Fig. 3C). These data not only establish DC as the main source of IL-12, but also indicate that through the production of this cytokine this cell population is the major initiator of protective immune responses against infections.

View larger version (16K): [in this window] [in a new window]   FIGURE 4. Adoptive transfer of IL-12p35–/– DCs failed to protect DC-depleted mice from T. gondii infection. CD11c-DTR-Tg mice were first injected with 100 ng DT at day –1. Six hours after DT injection, each mouse was given 107 DCs from either WT or IL-12p35–/– mice (as shown in Fig. 3A). At day 0, all mice were i.p. infected with 20 T. gondii brain cysts. Serum IL-12p70 levels at day 5 (A) or serum IFN- levels (B) were tested by ELISA. Sera from infected WT mice were used as control. Bars represent mean ± SE of the values obtained from at least three animal samples from each experimental group. C, Kaplan-Meier survival curve of DC recipient mice (n = 5 animals per group). Log-rank test; p = 0.005. Data shown are representative of at least three independent experiments.

	Discussion

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In summary, we show in this study that DCs are the main in vivo source of IL-12 during infection and that this response is critical for the development of protective immune responses against infection with the protozoan parasite, T. gondii.

	Acknowledgments

 
We thank Drs. Christopher Karp and Dragana Jankovic for critical reading of this manuscript.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Julio Aliberti, Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229. E-mail address: julio.aliberti{at}cchmc.org

² Abbreviations used in this paper: DC, dendritic cell; STAg, soluble Toxoplasma gondii Ag; DTR, diphteria toxin receptor; WT, wild type; LOD, low density.

Received for publication December 30, 2005. Accepted for publication April 26, 2006.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, C.-H. Articles by Aliberti, J. Search for Related Content PubMed PubMed Citation Articles by Liu, C.-H. Articles by Aliberti, J.