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Tyk2-Signaling Plays an Important Role in Host Defense against Escherichia coli through IL-23-Induced IL-17 Production by T Cells¹

Risa Nakamura^*, Kensuke Shibata^*, Hisakata Yamada^*, Kazuya Shimoda, Keiichi Nakayama and Yasunobu Yoshikai^2,*

^* Division of Host Defense, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and Department of Internal Medicine, Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Kiyotake, Miyazaki, Japan

	Abstract

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Tyrosine kinase 2 (Tyk2), a member of the JAK-signal transducer family, is involved in intracellular signaling triggered by various cytokines, including IL-23. We have recently reported that resident T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23. In this study, we examined importance of Tyk2-mediated signaling in the IL-17 production by T cells using Tyk2 deficient (–/–) mice. T cells in the peritoneal cavity of Tyk2^–/– mice displayed effecter/memory phenotypes and TCR V repertoire similar to those in Tyk2^+/+ mice and produced comparable level of IL-17 to those in Tyk2^+/+ mice in response to PMA and ionomycin, indicating normal differentiation to IL-17-producing effectors in the absence of Tyk2-signaling. However, T cells in Tyk2^–/– mice produced less amount of IL-17 in response to IL-23 in vitro than those in Tyk2^+/+ mice. Similarly, T cells in the peritoneal cavity of Tyk2^–/– mice showed severely impaired IL-17 production after an i.p. infection with E. coli despite comparable level of IL-23 production to Tyk2^+/+ mice. As a consequence, Tyk2^–/– mice showed a reduced infiltration of neutrophils and severely impaired bacterial clearance after Escherichia coli infection. These results indicate that Tyk2-signaling is critical for IL-23-induced IL-17 production by T cells, which is involved in the first line of host defense by controlling neutrophil-mediated immune responses.

	Introduction

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Interleukin 17A (IL-17A) is a T cell-derived cytokine exerting inflammatory effects including cytokine and chemokine production, which resulted in mobilization of neutrophils (1). IL-17 play essential roles in the host defense against various pathogens as well as in the pathogenesis of chronic inflammatory disorders (2). Helper CD4 T cells producing IL-17 were identified as a newly defined helper CD4 T cell subset, Th17. Although initial studies showed that the differentiation of Th17 cells was induced by IL-23, a heterodimeric cytokine composed of the p40 subunit of IL-12 and a unique p19 subunit (3, 4), it was later demonstrated that differentiation of Th17 cells was induced by IL-6 and TGF-β in mice (5). It is now generally believed that IL-23 rather provides a survival signal for already differentiated Th17 cells (6). In addition, it was also shown that IL-23-induced IL-17 production from memory/effector CD4 T cells (7, 8). IL-23 binds to its receptor composed of IL-12Rβ1 (also called as IL-23Rβ1) and IL-23R and shares the JAK-STAT signal pathway with IL-12 (9). However, signaling molecules critical for IL-17 production in response to IL-23 have not been identified.

Tyrosine kinase 2 (Tyk2)³ is a member of the JAK family and is activated in response to various cytokines including type 1 IFN, IL-6, IL-10, IL-12, and IL-13 (10). However, studies using Tyk2-deficient mice revealed different levels of dependence on Tyk2 between different cytokines (11, 12). Tyk2 was dispensable for IL-6- and IL-10-mediated signaling and was only partly required for signaling from type I IFN. In contrast, IL-12-mediated signaling, especially those for IFN- production by T cells, was highly dependent on Tyk2. As Tyk2 is recruited to IL-12Rβ1 (9), IL-23-mediated signaling also likely involves Tyk2. In fact, an impaired IL-23-induced phosphorylation of STAT3 was shown in Tyk2-deficient T cells (13), suggesting an importance of Tyk2 for IL-23-mediated signaling for IL-17 production.

T cells are widely distributed in nonlymphoid tissues and have been shown to be involved in host defense mechanism at an early phase of infection (14, 15, 16). We recently reported that an i.p. infection of Escherichia coli induced IL-17 production from resident peritoneal T cells expressing V1 TCR (17). IL-17 production by the T cells was mediated by IL-23 and was important for local neutrophil influx and protection against E. coli. In the present study, we examined the role of Tyk2 in IL-23-medaited signaling by using peritoneal T cells in Tyk2-deficient mice. Our results demonstrate that Tyk2 is not required for differentiation of T cells to produce IL-17 but is important for IL-17 production by T cells in response to IL-23 in vitro as well as in vivo.

	Materials and Methods

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Mice

Tyk2^–/– mice were generated as has been previously described (11) and have been backcrossed onto C57BL/6 mice more than eight times. The mice were bred under specific pathogen-free conditions in our institute. Six- to eight-week-old male mice were used for the experiments. This study was approved by the Committee of Ethics on Animal Experiment in Faculty of Medicine, Kyushu University. Experiments were conducted under the control of the Guidelines for Animal Experiment.

Microorganisms

E. coli (no. 26: American Type Culture Collection (ATCC), Rockville, MD) grown in trypto-soya broth (Nissui Pharmaceutical) was washed repeatedly, resuspended in 50% glycerol-containing PBS, and small aliquots were stored at –80°C until used. For all the experiments, mice were i.p. infected with 1 x 10⁸ CFU of E. coli.

Assessment of bacterial growth

At the indicated time after infection, the peritoneal contents were washed with 1 ml of HBSS and harvested after gentle massage. Samples were serially diluted with HBSS. The livers and spleens were removed and placed in homogenizers containing 3 ml of HBSS. Samples were spread on trypto-soya agar (Nissui Pharmaceutical) plates, and colonies were counted after incubation for 24 h at 37°C.

Measurement of IL-17 and IL-23 in peritoneal exudates

Supernatants of peritoneal exudates at indicated time points were obtained by centrifugation at 440 x g for 3 min at 4°C. IL-17 and IL-23 in the supernatant was measured by DuoSet ELISA Development System (R&D Systems) and Mouse IL-23 (p19/p40) ELISA Ready-Set-Go (eBioscience), respectively, according to manufacturer’s instructions.

RNA isolation, cDNA synthesis for RT-PCR, and TCR repertoire analysis

T cells in the peritoneal cavity were sorted using FACSAria (BD Biosciences) at the purity of >95%. mRNA of the purified T cells was extracted using TRIzol reagent (Invitrogen Life Technologies), and cDNA was synthesized using Superscript II (Invitrogen) according to the manufacturer’s instruction. For the V and V repertoire analysis, combinations of following primers were used: Forward primers: V 1/2, 5'-ACACAGCTATACATTGGTAC-3'; V2, 5'-CGGCAAAAAACAAATCAACAG-3'; V4, 5'-TGTCCTTGCAACCCCTACCC-3'; V5, 5'-TGTCCTTGCAACCCCTACCC-3'; V6, 5'-GGAATTCAAAAGAAAACATTGTCT-3'; V7, 5'-AAGCTAGAGGGGTCCTCTGC-3'; V1, 5'-ATTCAGAAGGCAACAATGAAAG-3'; V2, 5'-AGTTCCCTGCAGATCCAAGC-3'; V3, 5'-TTCCTGGCTATTGCCTCTGAC-3'; V4, 5'-CCGCTTCTCTGTGAACTTCC-3'; V5, 5'-CAGATCCTTCCAGTTCATCC-3'; V6, 5'-TCAAGTCCATCAGCCTTGTC-3'; V7, 5'-CGCAGAGCTGCAGTGTAACT-3'; V8, 5'-AAGGAAGATGGACGATTCAC-3'; Reverse primers: C, 5'-CTTATGGAGATTTGTTTCAGC-3'; C, 5'-CGAATTCCACAATCTTCT-3'. PCR was performed on a PCR thermal cycler (Takara Corporation). For the southern blot analysis, PCR products were transferred to a Gene Screen Plus filter (New England Nuclear). The following oligonucleotide probes were used: C (5'-AAGGAACAAAGCTCATAGTAATTCCCTCCGACAAAAGGCT-3'), J1 (5'-TTGGTTCCACAGTCACTTGG-3'), and J2 (5'-CTCCACAAAGAGCTCTATGCCCA-3'). The oligonucleotide probes were labeled with [-³²P] ATP using a Megalabel 5'-labeling kit (Takara Shuzo) according to the manufacturer’s instructions. Before hybridization, the filters were incubated in 1 M NaCl, 1% SDS, 10% dextran sulfate, and 50 µg/ml heat-denatured salmon sperm DNA for 18 h at 65°C, and then the filters were washed in 2 x SSC, 1% SDS for 15 min at 65°C. The radioactivity of each band of PCR product was analyzed with a Fujix BAS2000 Bio-Image analyzer (Fuji Photo Film). Real-time PCR was conducted by using ABI PRISM7000 Sequence Detection System (Applied Biosystems) and Power SYBR Green PCR Master Mix (Applied Biosystems). The following pairs of specific primers were used: IL-23R, 5'-TGAAAGAGACCCTACATCCCTTGA-3', 5'-CAGAAAATTGGAAGTTGGGATATGTT-3'; GAPDH, 5'-TGGTGAAGGTCGGTGTGAAC-3', 5'-CCATGTAGTTGAGGTCAATGAAGG-3'. Each gene expression was normalized with GAPDH mRNA content. "Fold differences" were calculated with the ^Ct method.

Abs and flow cytometric analysis

Peritoneal exudate cells (PEC), splenocytes, lung and liver mononuclear cells, lamina propria lymphocytes (LPL), and intraepithelial lymphocytes (IEL) were collected as described previously (18, 19, 20) and stained with mAbs described below. FITC-conjugated anti-TCR mAb (GL3), PerCP-Cy5.5-conjugated anti-CD3 mAb, and PE-conjugated anti-mIL-17 (TC11–18H10.1) mAb were purchased from BD Biosciences. FITC-conjugated anti-Ly-6C mAb (AL-21), PE-conjugated anti-Gr1 mAb (RB6–8C5), allophycocyanin-conjugated anti-CD3 mAb (145–2C11), anti-CD44 mAb (IM-7), biotin-conjugated anti-CD4 mAb (L3T4), and PerCP-conjugated streptavidin were purchased from eBioscience. Biotin-conjugated anti-TCR mAb (GL3) was purchased from Caltag Laboratories. Stained cells were run on a FACSCalibur flow cytometer (BD Biosciences). The data were analyzed using CellQuest software (BD Biosciences). To calculate cell numbers in each organ by using flow cytometer, we first applied a standard sample of known cell concentration and then ran the test samples at a same flow rate for a constant acquisition time.

Intracellular cytokine staining

For ex vivo intracellular cytokine staining, PEC were collected 6 h after infection with E. coli and then were incubated with 10 µg/ml brefeldin A (Sigma-Aldrich) for 1 h. For intracellular cytokine staining of in vitro stimulated cells, PEC from naive mice were used for the experiments. Cells were stimulated with or without 2 ng/ml or 20 ng/ml rIL-23 (R&D Systems) or 10 ng/ml PMA (Sigma-Aldrich) and 1 µg/ml ionomycin (Sigma-Aldrich) for 7 h in a CO₂ incubator at 37°C. Ten µg/ml brefeldin A was added for the last 5 h incubation. Cells were stained with allophycocyanin- conjugated CD3, FITC-conjugated anti-TCR mAb for 30 min at 4°C. Thereafter, intracellular staining was performed according to the manufacturer’s instructions (BD Biosciences). In brief, 100 µl of BD Cytofix/Cytoperm solution (BD Biosciences) was added to the cell suspension with mild mixing and placed for 20 min at 4°C. Fixed cells were washed with 250 µl of BD Perm/Wash solution (BD Biosciences) twice and were stained intracellularly with PE-conjugated anti-mIL-17 mAb for 30 min at 4°C. Stained cells were run on a FACSCalibur flow cytometer (BD Biosciences). The data were analyzed using CellQuest software (BD Biosciences).

Statistics

Statistical significance was calculated by the Student’s t test using Prism software (GraphPad). Differences with p values of <0.05 were considered statistically significant.

	Results

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Development of T cells in Tyk2^–/– mice

We first examined the number of TCR T cells in various organs in naive Tyk2^–/– mice. As shown in Fig. 1, the number of T cells in the peritoneal cavity and intestinal lamina propria was significantly lower in Tyk2^–/– mice than Tyk2^+/+ mice (p < 0.05). In contrast, the numbers of T cells in the spleen, thymus, lung, liver, and IEL in Tyk2^–/– mice were not different from those in Tyk2^+/+ mice (Fig. 1, data not shown). Most of the T cells in the peritoneal cavity of naive Tyk2^–/– mice showed CD44⁺ memory phenotype similar to those in Tyk2^+/+ mice (Fig. 2A). Percentage of Ly-6C positive cells in the peritoneal T cells in Tyk2^–/– mice was much the same as that in Tyk2^+/+ mice. There was also no difference in the expression of other surface markers including CD62L, CD122, CD25, and CD69 (data not shown). Expression of IL-23R in purified T cells from the peritoneal cavity was quantitatively examined by real-time RT-PCR. As shown in Fig. 2B, T cells in naive Tyk2^–/– mice expressed IL-23R comparable to those in control mice. As we had found T cells bearing V1 was responsible for IL-17 production (17), TCR V repertoire of the TCR T cells was also analyzed by RT-PCR followed by Southern blotting. As shown in Fig. 2C, T cells in the peritoneal cavity of Tyk2^–/– mice exclusively expressed V6 gene and V1 gene rearranged to the J2 gene, and those in Tyk2^+/+ mice preferentially expressed V6 and V1 in addition to V1, V2, V4, and V6. Thus, although the number of T cells in the peritoneal cavity was decreased in Tyk2^–/– mice, the T cells in Tyk2^–/– mice were virtually indistinguishable from those in control mice in regard to the expression of surface markers, IL-23R, and TCR V6 and V1 genes.

View larger version (15K): [in this window] [in a new window]   FIGURE 1. Development of T cells in Tyk2–/– mice. Absolute number of T cells (GL-3 positive) in PEC (A), spleen (B), lung (C), liver (D), LPL (E), and IEL (F) of naive Tyk2+/+ or Tyk2–/– mice were measured by using flow cytometry. Data are the means ± SD of four to six mice for each group; *, p < 0.05. Representatives of three independent experiments are shown.

View larger version (28K): [in this window] [in a new window]   FIGURE 2. Characterization of T cells in the peritoneal cavity of naive Tyk2–/– mice. A, Expression of CD44 and Ly6c on T cells in the peritoneal cavity of naive mice were examined by flow cytometry. B, T cells were FACS sorted and expression of IL-23R was analyzed by real-time RT-PCR. C, TCR V (upper panels) and V gene (lower panels) expression in the purified T cells was analyzed by Southern blotting. Data are representatives of three independent experiments.

In vitro IL-17 production by T cells from the peritoneal cavity of naive Tyk2^–/– mice

We next examined the ability of the T cells in the peritoneal cavity to produce IL-17 by intracellular staining. As shown in Fig. 3A, the level of IL-17 production was significantly lower in T cells in Tyk2^–/– mice in response to exogenous IL-23, although the difference in the percentage of IL-17-producing T cells between Tyk2^–/– mice and Tyk2^+/+ mice was lesser in response to higher amounts of exogenous IL-23. However, most of peritoneal T cells of not only Tyk2^+/+ mice but also Tyk2^–/– mice produced IL-17 in response to PMA and ionomycin (Fig. 3B). These results suggest that Tyk2-signaling is dispensable for differentiation of peritoneal T cells to IL-17-producing effectors but is important for IL-17 production by T cells in response to IL-23. In contrast to the T cells in PEC, only a limited percentage of T cells in the spleen, thymus, lung, and liver produced IL-17 in response to PMA and ionomycin in both Tyk2^+/+ mice and Tyk2^–/– mice (Fig. 3B, data not shown). IL-17-producing T cells were nearly absent in IEL, whereas they were abundantly found in LPL.

View larger version (27K): [in this window] [in a new window]   FIGURE 3. IL-17 production by peritoneal T cells in Tyk2–/– mice in vitro. A, PEC from Tyk2+/+ (left) or Tyk2–/– mice (right) was stimulated with rIL-23 (2 ng/ml or 20 ng/ml) for 7 h. B, PEC, splenocytes, liver mononuclear cells, LPL, and IEL were stimulated with 10 ng/ml PMA and 1 µg/ml ionomycin for 7 h. Brefeldin A was added to all the cultures for the last 5 h, and cells were tested for intracellular staining of IL-17. The numbers in the upper right quadrants indicate the percentage of IL-17-positive cells in T cells. Data are representatives of three independent experiments.

In vivo IL-17 production by the T cells in Tyk2^–/– mice following E. coli infection

To determine in vivo significance of Tyk2-signaling for IL-17 production by T cells, we injected E. coli i.p. into Tyk2^–/– mice. IL-17-producing T cells were detected after a brief ex vivo culture with brefeldin A, which were clearly reduced in Tyk2 ^–/– mice. As reported previously, IL-17-producing cells were hardly found other than T cells (Ref. 17 and data not shown). We also measured the amount of cytokines in the peritoneal cavity of E. coli infected mice. IL-17 production was severely impaired in Tyk2^–/– mice, although IL-23 production in the peritoneal cavity of Tyk2^–/– mice was comparable to those in Tyk2^+/+ mice (Fig. 4B). Consistent with the previous report (17), infiltration of neutrophils in the peritoneal cavity, which reached the peak at 24 h after infection, was observed in both Tyk2^+/+ and Tyk2^–/– mice, but the number of neutrophils was significantly reduced in Tyk2^–/– mice (Fig. 4C, left). Furthermore, Tyk2^–/– mice showed significantly impaired bacterial clearance in peritoneal cavity (p < 0.01) (Fig. 4C, right). We also found significantly increased bacterial burden in the spleen (p < 0.05) and the liver (p < 0.05) of Tyk2 ^–/– mice (data not shown). These results clearly demonstrated in vivo significance of Tyk2-signaling for the host defense against E. coli through IL-23-induced IL-17 production by T cells.

View larger version (22K): [in this window] [in a new window]   FIGURE 4. IL-17 production by peritoneal T cells in Tyk2–/– mice in vivo after E. coli infection. Tyk2–/– mice were i.p. inoculated with 1 x 108 CFU of E. coli. A, After 6 h, PEC was tested for ex vivo intracellular staining for IL-17. The numbers in the upper right quadrants indicate the percentage of IL-17 positive cells in T cells. Data were representative of three independent experiments. B, IL-17 (left) and IL-23 (right) in peritoneal exudates were measured by ELISA at 6 h after E. coli infection. C, Number of neutrophils (left) and bacteria (right) in PEC at 24 h after E. coli infection were measured. Data are the means ± SD of three to six mice for each group; *, p < 0.05; **, p < 0.01. Representatives of three independent experiments are shown.

	Discussion

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The lack of IL-17 production in response to IL-23 by T cells in Tyk2^–/– was not attributed to a defect in differentiation to IL-17-producing effector cells, because normal IL-17 production by T cells in Tyk2^–/– mice was induced by stimulation with PMA and ionomycin. Furthermore, T cells in Tyk2^–/– mice were indistinguishable from those in Tyk2 mice in effector/memory phenotype and the expression of IL-23R. They expressed V6 and V1, which we have demonstrated to be the major IL-17-producing T cell repertoire in the PEC of wild-type mice (17). These results suggest that the peritoneal T cells differentiate into IL-17-producing effectors in situ in the absence of Tyk2. At present, it is unclear what factors are required for differentiation of T cells to produce IL-17. In the case of CD4 T cells, it is generally accepted that TGF-β in combination with IL-6 induces differentiation of Th17 cells (5). Interestingly, it was shown that an absence of Tyk2 did not affect the phosphorylation of STAT3 by IL-6 (12). Thus, it is speculated that the factors involved in the differentiation of IL-17-producing T cells are not affected by the absence of Tyk2.

IL-23 was initially demonstrated to induce differentiation of Th17 cells, but is currently thought to be involved in maintenance (expansion or survival) of Th17 cells (5). In this regard, it is of note that the number of T cells in the peritoneal cavity and LPL of naive Tyk2^–/– mice were significantly lower than Tyk2^+/+ mice, whereas the number of T cells in spleen, thymus, lung, liver, and IEL, which contain relatively a small number of IL-17-producing cells, was not significantly different between Tyk2^+/+ and Tyk2^–/– mice. This supports an involvement of Tyk2 in IL-23-mediated signaling for selective maintenance of IL-17-producing T cells. However, we have not detected mitogenic or anti-apoptotic effect of IL-23 on T cells in vitro as yet. It is also possible that Tyk2 is directly involved in the development of peritoneal T cells by other mechanisms. Further studies are needed to clarify these issues. IL-23 was also shown to augment IL-17 production from activated/memory CD4 T cells (7, 8, 24). Therefore, resident T cells are similar to activated/memory CD4 T cells not only in the expression pattern of surface molecules but also in the way to exert their effector functions in response to IL-23, although stimulation with IL-23 alone is insufficient to induce IL-17 production in the case of CD4 T cells (our unpublished data).

Although T cells from Tyk2^–/– mice displayed severely reduced responsiveness to a small amount of IL-23, a high concentration of IL-23 partly restored their ability to produce IL-17. It was demonstrated that Tyk2 was partially involved in type I IFN-mediated signaling, whereas IL-12-mediated cellular responses were highly dependent on Tyk2. Defective phosphorylation of Stat 4 or Stat3 in response to IL-12 was also demonstrated. However, it was also shown that a higher dose of IL-12 overcame the effect of Tyk2 deficiency on the differentiation of Th1 cells (11), similar to the case of IL-23 in this study. Leaky expression of neither Tyk2 protein nor Tyk2 mRNA was detected in Tyk2^–/– mice (Ref. 11 and data not shown). Therefore, it is possible that other JAKs, likely JAK2, compensate for the defect of Tyk2 to respond to a high dose of the cytokines. Nevertheless, our in vivo data showing severely reduced IL-17 production during E. coli infection indicate that IL-23-signaling is highly dependent on Tyk2 in physiological conditions.

Recently, a patient with homozygous mutation of Tyk2, which causes a loss of Tyk2 protein, was reported (25). The patient was clinically diagnosed as hyper IgE syndrome and showed susceptibility to various types of pathogens including virus, fungi, and intracellular and extracellular bacteria. Interestingly, Tyk2 deficiency in human showed severely impaired responses not only to IL-12 but also to type I IFN, IL-6, and IL-10, in contrast to Tyk2-deficient mice. An abolished phosphorylation of Stat4 and IFN- production in response to IL-23 was also shown using T cells from the patient. In this study, we speculate that an impaired IL-17 production in response to IL-23 might also be involved in the immunodeficient phenotype of the patient, as we demonstrated in this study by using Tyk2^–/– mice. Further studies will uncover in vivo roles of Tyk2 in different aspects of immune responses.

	Acknowledgments

 
We thank Kazue Kaneda and Hideki Oimomi for providing technical support.

	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 This work is partly supported by Grant-in Aid for Scientific Research on Priority Areas, Japan Society for the Promotion of Science.

² Address correspondence and reprint requests to Dr. Yasunobu Yoshikai, Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan. E-mail address: yoshikai{at}bioreg.kyushu-u.ac.jp

³ Abbreviations used in this paper: Tyk2, tyrosine kinase 2; PEC, peritoneal exudate cell; LPL, lamina propria lymphocyte; IEL, intraepithelial lymphocyte.

Received for publication November 2, 2007. Accepted for publication June 2, 2008.

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Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 

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