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T Cells Control Early Infiltration of Neutrophils after Escherichia coli Infection via IL-17 Production1
* Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan;
Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan; and
Department of Immunology and Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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Abstract |
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T cell population was the major source of IL-17. Mice depleted of T cells by mAb treatment or mice genetically lacking V1 showed diminished IL-17 production and reduced neutrophil infiltration after E. coli infection, indicating an importance of V1+ T cells as the source of IL-17. It was further revealed that T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23, which was induced rapidly after E. coli infection in a TLR4 signaling-dependent manner. Thus, although T cells are generally regarded as a part of early induced immune responses, which bridge innate and adaptive immune responses, our study demonstrated a novel role of T cells as a first line of host defense controlling neutrophil-mediated innate immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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IL-17 (also known as IL-17A) is a T cell-derived proinflammatory cytokine, which is involved in accumulation and activation of neutrophils (7, 8). IL-17 induces mobilization of neutrophils indirectly via production of several cytokines, CSFs, and C-X-C chemokines (9). It is generally accepted that IL-17 production by memory T cells is regulated by IL-23, whereas TGF-
in combination with IL-6 is critical for the development of IL-17-producing Th cells from naive CD4 T cells (10, 11, 12). Involvement of both TCR
and TCR T cells was suggested to be involved in the IL-17-induced homeostatic control of granulopoiesis (13). Important roles of IL-17 in a murine model of pulmonary infection with Klebsiella pneumoniae were recently demonstrated (14, 15). In this model, both CD4 and CD8 T cells were identified as cellular source of IL-17. IL-17 receptor-deficient mice showed a markedly decreased neutrophil recruitment to the lung and an impaired host defense against K. pneumoniae (16). IL-23 knockout mice also showed increased susceptibility to K. pneumoniae infection, which was most likely due to a reduced production of IL-17 (15). Similarly, IL-17 plays an essential role in neutrophil recruitment in the airway after endotoxin inhalation (17). CD4 T cell-derived IL-17 was shown to mediate intra-abdominal abscess formation in response to Bacteroides fragilis (18). Importance of IL-17 in inflammatory responses has been analyzed more extensively in murine models of autoimmune diseases, including arthritis, encephalomyelitis, and colitis (19, 20, 21, 22). In these situations, induction of pathogenic CD4 T cells producing IL-17, which was promoted by IL-23, was critical for the development of the disease.
We and others have analyzed host defense mechanisms against extracellular bacteria using murine models of i.p. infection with Escherichia coli (23, 24, 25, 26). Although it is well established that neutrophils are essential in bacterial clearance, roles of IL-17 in this model are unknown. In this study, we found a rapid production of IL-17 after i.p. infection with E. coli, which was critical for the local infiltration of neutrophils and host defense. Unexpectedly, T cells, especially those bearing V1, were the major source of the early IL-17 production and were indeed critical for the neutrophil infiltration after E. coli infection. These findings provide new insights in the functions of T cells as well as in innate immune responses against bacterial infection.
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Materials and Methods |
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C57BL/6, C3H/HeN, and C3H/HeJ mice were purchased from Japan SLC. V1-deficient mice were generated, as previously described (27). These mice were bred in specific pathogen-free conditions in our institute. Six- to 8-wk-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 Guideline for Animal Experiment.
Microorganisms
E. coli (no. 26; American Type Culture Collection (ATCC)) grown in Trypto-Soya broth (Nissui Pharmaceutical) was washed repeatedly and resuspended in 50% glycerol-containing PBS, and small aliquots were stored at –80°C until used. For all of 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 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 in peritoneal fluid
Supernatants of peritoneal exudates at indicated time points were obtained by centrifugation at 440 x g for 3 min at 4°C. IL-17 in the supernatant was measured by DuoSet ELISA Development System (R&D Systems), according to manufacturer’s instruction.
RNA isolation, cDNA synthesis, and real-time PCR
Total RNA from peritoneal exudate cells (PEC)3 at each point was extracted using TRIzol reagent (Invitrogen Life Technologies). The first-stranded cDNA synthesis was done using Superscript I (Invitrogen Life Technologies), according to manufacturer’s instruction. Real-time PCR was conducted by ABI PRISM7000 Sequence Detection System (Applied Biosystems), using Power SYBR Green PCR Master Mix (Applied Biosystems) and gene-specific primers, as follows: IL-23p19, 5'-GGGAACAAGATGCTGGATT-3' and 5'-CTTCACACTGGATACGGGG-3'; GAPDH, 5'-GGCAAATTCAACGGCACA-3' and 5'-GTTAG TGGGGTCTCGCTCTG-3'.
Thermal cycling conditions were 10 min at 95°C, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. SYBR Green dye intensity was analyzed using the ABI Prism 7000 SDS software. Each gene expression was normalized with GAPDH mRNA content. Fold differences were calculated with the 
Ct method.
In vivo blockade of IL-17
One hour before i.p. infection with E. coli, 200 µg/mouse anti-murine IL (mIL)-17 mAb (clone 50104; R&D Systems) was i.p. administered. As a control, 200 µg/mouse isotype-matched rat IgG2a mAb (eBioscience) was used.
In vivo depletion of T cells
Seven days after injecting 250 µg of anti-TCR mAb (UC7-13D5), when there remained no possible stimulatory effect of the Ab, but T cells were still completely depleted, mice were injected i.p. with E. coli. UC7-13D5 has been widely used for depleting T cells (28) and was provided by J. Bluestone (University of California, San Francisco, CA). As a control, 250 µg/mouse isotype-matched anti-dinitrophenol hamster IgG mAb, UC8-1B9 (ATCC), was used.
Abs and flow cytometric analysis
PEC and splenocytes were collected and stained with various mAbs, as described below. FITC-conjugated anti-TCR (GL3), anti-TCR (H57-597), and anti-Gr1 (RB6-8C5) mAbs; allophycocyanin-conjugated anti-CD3
(145-2C11); anti-CD44 (IM-7) mAb; and allophycocyanin-conjugated streptavidin were purchased from eBioscience. Biotin-conjugated anti-TCR (GL3) mAb was purchased from Caltag Laboratories. PerCP-conjugated anti-CD3 mAb and PE-conjugated anti-mIL-17 (TC11-18H10.1) mAb were purchased from BD Biosciences. Stained cells were run on a FACSCalibur flow cytometer (BD Biosciences). The data were analyzed using CellQuest software (BD Biosciences).
In vitro measurement of IL-17 production by PEC
Whole or T cell-depleted PEC were stimulated with 1 µg/ml LPS (Sigma-Aldrich) for 24 h in CO2 incubator at 37°C. IL-17 in the supernatants was measured by DuoSet ELISA Development System (R&D Systems). To purify or deplete T cells, PEC from E. coli-infected mice were first incubated with FITC-conjugated anti-TCR mAb and then with MACS beads conjugated with anti-FITC mAb (Miltenyi Biotec). Stained cells were positively or negatively selected using MACS columns following manufacturer’s protocol (Miltenyi Biotec). The efficiency of T cell purification or depletion was determined by flow cytometry analysis.
Intracellular cytokine staining
Ex vivo intracellular cytokine staining was performed, as previously reported (29). Briefly, 500 µl of 0.5 mg/ml brefeldin A (Sigma-Aldrich) was i.p. injected at 2 h after E. coli infection. PEC was collected at 5 h after infection and used for intracellular cytokine-staining analysis. For in vitro assay, PEC was stimulated with or without 1 ng/ml rIL-23 (R&D Systems), 1 ng/ml rTGF-1 (PeproTech), 20 ng/ml rIL-6 (PeproTech), or 1 µg/ml LPS (Sigma-Aldrich) for 7 h in CO2 incubator at 37°C. In some experiments, 10 µg/ml anti-mIL-23R mAb (clone 258010; R&D Systems) was added to the culture. A total of 10 µg/ml brefeldin A was added for the last 5-h incubation. Cells were stained with allophycocyanin-conjugated CD3, FITC-conjugated anti-TCR mAb, or anti-TCR mAb for 30 min at 4°C. Thereafter, intracellular staining was performed according to manufacturer’s instruction (BD Biosciences). Briefly, 100 µl of BD Cytofix/Cytoperm solution (BD Biosciences) was added to cell suspension with mild mixing, 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.
CFSE labeling and mixed cell culture
PEC from C3H/HeN or C3H/HeJ mice were labeled with 0.01 µM CFSE (Molecular Probes) for 15 min at 37°C in a CO2 incubator. PEC from C3H/HeJ mice were mixed at the ratio of 1:1 with the labeled cells from C3H/HeN or C3H/HeJ mice and incubated for 7 h at 37°C in a CO2 incubator. Brefeldin A (0.5 mg/ml) was added to 10 µg/ml final concentration for last 5-h incubation. Cells were stained with biotin-conjugated TCR mAb, PerCP-conjugated CD3 mAb, and allophycocyanin-conjugated streptavidin. IL-17 production from T cells was analyzed by the intracellular staining method described above.
Statistics
Statistical significance was calculated by Student’s t test using Prism software (GraphPad). Differences with p values of <0.05 were considered statistically significant.
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Results |
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We first examined the kinetics of local neutrophil infiltration during i.p. infection with E. coli in C57BL/6 mice. Consistent with the previous report (26), rapid infiltration of neutrophils in the peritoneal cavity, which reached the peak at 24 h after infection, was observed (Fig. 1A). IL-17 production in the peritoneal cavity reached the peak at 6 h after i.p. infection with E. coli, and was rapidly ceased (Fig. 1B). We also performed real-time quantitative PCR analysis on the mRNA expression of IL-23 p19. An increased expression of IL-23 p19 was observed with the peak at 2 h after i.p. infection with E. coli (Fig. 1C). These results suggest an involvement of IL-17 and IL-23 in the local infiltration of neutrophils after infection with E. coli.
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To directly examine in vivo significance of the early IL-17 production, we pretreated the mice with anti-mIL-17 mAb before i.p. infection with E. coli. As shown in Fig. 2A, infiltration of neutrophil was significantly reduced by the anti-mIL-17 mAb pretreatment. Blocking IL-17 also significantly impaired bacterial clearance in the peritoneal cavity and the liver (Fig. 2B). These results clearly demonstrated that the rapid production of IL-17 after E. coli infection was critical for the infiltration of neutrophils, leading to bacterial clearance.
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T cells after E. coli infection
To identify the cell subset(s) responsible for the early IL-17 production in vivo, we injected brefeldin A in the peritoneal cavity of C57BL/6 mice 2 h after i.p. infection with E. coli. PEC were harvested 5 h later and were examined for intracellular staining for IL-17. IL-17-producing cells were CD3 positive, but were not positive for TCR (Fig. 3, A and B). It was revealed that most of the IL-17-producing cells expressed TCR. TCR T cells produced IL-17 in response to E. coli infection, because IL-17-producing cells were hardly found in the PEC from naive mice that were also injected with brefeldin A (Fig. 3A).
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T cells are responsible for the IL-17 production and neutrophil infiltration after E. coli infection
To examine involvement of T cells in IL-17 production and neutrophil infiltration after E. coli infection in vivo, mice were infected i.p. with E. coli after T cells were depleted by injecting an anti-TCR mAb, UC7-13D5 (Fig. 4A). There was significant reduction in the concentration of IL-17 in the T cell-depleted mice (Fig. 4B). The number of neutrophils infiltrated in the peritoneal cavity 24 h after E. coli infection was significantly reduced in these mice (Fig. 4B). Thus, it was revealed that T cells were responsible for the early IL-17 production and mobilization of neutrophils after E. coli infection.
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T cells bearing invariant V6/V1 significantly increased in the peritoneal cavity after i.p. infection with E. coli (23, 24, 25, 26), we further examined the IL-17 production and neutrophil infiltration in V1–/– mice. Although there was no difference in the number of T cells between naive V1+/– and V1–/– mice, IL-17 production 6 h after i.p. infection with E. coli was significantly reduced in V1–/– mice compared with V1+/– mice (Fig. 4C). Consistently, the neutrophil infiltration 24 h after infection was also reduced in V1–/– mice (Fig. 4C), suggesting that V1+ cells predominantly participate in the early IL-17 production, which induces infiltration of neutrophils, after E. coli infection. The rapid IL-17 production after E. coli infection is TLR4 signaling dependent
To examine involvement of TLR4-mediated recognition of E. coli in the IL-17 production, we compared immune responses after i.p. infection with E. coli between C3H/HeN and C3H/HeJ mice; the latter have a defect in TLR4 signaling. Similar to the case of C57BL/6 mice, IL-17 production was detected in the peritoneal exudates of C3H/HeN mice at 6 h after infection with E. coli, whereas IL-17 production was completely abolished in C3H/HeJ mice (Fig. 5A). Consistently, infiltration of neutrophil was also strikingly diminished in C3H/HeJ mice (Fig. 5B). Thus, TLR4-mediated signaling is indispensable for the early IL-17 production following i.p. E. coli infection. Because LPS in the cell wall of Gram-negative bacteria such as E. coli stimulates TLR4, we stimulated PEC from naive C3H/HeN mice with LPS in vitro and examined IL-17 production by the intracellular staining method. Similar to the case of in vivo infection with E. coli, most of the IL-17-producing cells in response to LPS stimulation in vitro were T cells (Fig. 5C). To confirm secretion of IL-17 by T cells, we also measured IL-17 by ELISA. Significant amount of IL-17 was detected in the culture supernatant of PEC from naive mice after stimulation with LPS, which was reduced by depleting T cells (Fig. 5D). These results indicated that T cells that reside in the peritoneal cavity of naive mice rapidly secrete IL-17.
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T cells themselves or other cell populations in the PEC, we set up the following experiment. PEC from LPS-nonresponsive C3H/HeJ mice were stimulated in vitro with LPS in the presence of CFSE-labeled PEC from C3H/HeJ mice or LPS-responsive C3H/HeN mice, and then IL-17 production was analyzed. IL-17 production by the CSFE-negative T cells from C3H/HeJ mice was clearly detected when they were cocultured with PEC from C3H/HeN mice, but not with those from C3H/HeJ mice (Fig. 6). Therefore, it was revealed that the LPS-induced IL-17 production by the PEC-resident T cells required functional TLR4 signaling in other cell populations than T cells themselves.
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T cells was induced by IL-23-mediated signaling
Above results suggested that the IL-17 production by T cells requires some factor(s) provided by LPS-stimulated PEC. As shown in Fig. 1C, IL-23 was also produced rapidly in the peritoneal cavity of C57BL/6 mice after infection with E. coli. Unlike C3H/HeN mice or C57BL/6 mice, IL-23 p19 mRNA was not up-regulated in C3H/HeJ mice after infection (data not shown). Therefore, we addressed an involvement of IL-23 in the LPS-induced IL-17 production by T cells by adding neutralizing mAb against IL-23 in the culture (Fig. 7A). It was revealed that blocking IL-23 significantly reduced the IL-17 production by T cells. We also examined the ability of exogenous IL-23 to stimulate T cells. In vitro culture with IL-23 indeed induced IL-17 production by the resident T cells in the peritoneal cavity of naive mice (Fig. 7B). Secretion of IL-17 by these T cells was confirmed by measuring concentration of IL-17 in the culture supernatants of purified T cells stimulated with IL-23 (Fig. 8). Recently, it was shown that naive CD4 T cells stimulated with TGF- in the presence of IL-6 differentiated into IL-17-producing Th17 cells (12). However, TGF- in combination with IL-6 failed to stimulate IL-17 production by T cells (Fig. 7B). Thus, T cells behave more like IL-17-producing memory T cells. In support of this, almost all T cells residing in peritoneal cavity of naive mice are CD44high (Fig. 7C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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T cells in the infiltration of neutrophils following i.p. infection with E. coli, through IL-17 production. Rapid IL-17 production by PEC T cells was detected not only in C57BL/6 mice or C3H mice, but also in BALB/c mice (data not shown). This was not due to an artificial specific pathogen-free environment, because PEC T cells in C57BL/6 mice maintained in conventional environment also rapidly produced IL-17 (data not shown).
IL-17 has been shown to control the local accumulation of neutrophils. Laan et al. (7) found intratracheal instillation of IL-17 selectively recruited neutrophils in rat airways, which were mediated by MIP-2. Witowski et al. (30) directly showed an i.p. injection of IL-17-induced local infiltration of neutrophils, which is mediated by growth-related oncogene chemokine. Roles of IL-17 in infiltration of neutrophils and host defense have been well studied in murine models of pulmonary infection with K. pneumoniae. IL-17R-deficient mice were highly sensitive to pulmonary K. pneumoniae infection (16). They showed reduced G-CSF and MIP-2 production, which resulted in reduced recruitment of neutrophils in the lung. We found in this study that IL-17 plays critical roles in neutrophil infiltration also in i.p. infection with E. coli. IL-17 has also been shown to be involved in autoimmune disease, such as rheumatoid arthritis (22). It is of note that the majority of the infiltrating cells in the synovial fluid of rheumatoid arthritis are neutrophils. Furthermore, involvement of IL-17 airway inflammation in humans has also been shown (31, 32, 33). Taken together, these findings suggest that IL-17 is generally involved in neutrophil-mediated immune responses.
We have previously reported an increase of T cells during i.p. inoculation with E. coli (23, 24, 25, 26). After i.p. inoculation with E. coli, these T cells gradually increase even after the bacteria had almost been cleared from their body (23). They participated in the recruitment and activation of macrophages via producing CC chemokines and IFN- (26). In this study, we found V1+ T cells were also involved in the infiltration of neutrophils at the early stage of E. coli infection, when the number of T cells was still at baseline, via producing IL-17. At present, it is unclear whether the same V1+ T cells participate in both situations. Resident V1+ T cells may have different function from the induced V1+ T cells. Alternatively, the different functions may be resulted from different stimuli, particularly IL-12 and IL-23 for IFN- and IL-17 production, respectively. It is notable that IL-17 production by resident T cells was stimulated with IL-23 alone, suggesting that TCR-mediated recognition of bacterial Ags and expansion are not required for the response.
Host defense mechanisms against Gram-negative bacteria, which include neutrophil mobilization, are triggered by TLR-4-mediated pathogen recognition by tissue-resident macrophages (34). In this study, we demonstrated that E. coli-induced IL-17 production by T cells was triggered by TLR-4-mediated signaling. Happel et al. (14) also showed TLR-4 signaling was indispensable for IL-17 as well as IL-23 production after pulmonary infection with K. pneumoniae. In vitro analysis revealed that TLR-4 signaling is not required for the T cells themselves (Fig. 6). T cells rather receive some signals/factors, most likely IL-23, from TLR-4-stimulated surrounding cells, including macrophages. LPS-induced IL-17 production of PEC T cells was abrogated by blocking IL-23. IL-23 directly induced IL-17 production by PEC T cells (Fig. 7B). Taken together, these findings revealed a novel pathway of TLR-4 signaling-induced neutrophil infiltration, which is mediated by IL-23 and IL-17.
It was recently reported that the developmental pathway of IL-17-producing CD4 T cells is related with immunoregulatory CD4 T cells under the control of TGF- (12, 35). This raises a possibility that similar developmental control is applicable for T cells, which have been shown in either protective against infection or immunoregulative (36).
Although we found TGF- and IL-6, which has been shown to induce differentiation of IL-17-producing effector CD4 T cells from naive CD4 T cells, did not induce IL-17 production by PEC T cells, this might be because these T cells had already differentiated into IL-17-secreting memory T cells in situ, which are sensitive for IL-23. Expression of memory markers on the PEC T cells in naive mice also supports this possibility. However, it is still possible that TGF- is involved in their functional differentiation.
Literature describes roles of T cells as the first line of host defense, which has been supposed mainly by their anatomical location in peripheral tissues, including epidermis. However, most of the studies on the roles of T cells in the epithelium rather revealed their immunoregulatory properties (36, 37). In this study, we clearly demonstrated an involvement of resident T cells at the very early stage of host defense against bacterial infection through IL-17 production. It is of interest to further examine the development and functions of resident T cells in other tissues/organs.
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Acknowledgments |
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mAb (UC7-13D5). We also thank K. Hirowatari for preparing the manuscript and Y. Tagawa for helpful technical assistance. |
Disclosures |
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Footnotes |
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1 This work was supported by the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases, which was launched as a project commissioned by the Ministry of Education, Culture, Sports, Science, and Technology, Japan; by Grant-in-Aid for Japan Society for Promotion of Science; and by grants from the Japanese Ministry of Education, Science, and Culture (to Y.Y.). 
2 Address correspondence and reprint requests to Dr. Hisakata Yamada, Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: hisakata{at}bioreg.kyushu-u.ac.jp
3 Abbreviations used in this paper: PEC, peritoneal exudate cell; Ct, cycle threshold; mIL, murine IL.
Received for publication August 22, 2006. Accepted for publication January 22, 2007.
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References |
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in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179-189. [Medline] T cells induced by Escherichia coli infection in mice: correlation between Thy-1 phenotype and host minor lymphocyte-stimulating phenotype. J. Immunol. 151: 2062-2069. [Abstract] T cells at the infected site. Eur. J. Immunol. 29: 3877-3886. [Medline] T cells bearing invariant V6/V1 induced by Escherichia coli infection in mice. J. Immunol. 165: 931-940. 1+ T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice. J. Immunol. 173: 5156-5164. TCRs in V1-deficient mice. J. Immunol. 165: 3695-3705. T cells in primary infection with Listeria monocytogenes in mice. J. Exp. Med. 175: 49-56. chemokine from mesothelial cells. J. Immunol. 165: 5814-5821. T cells. Nat. Rev. Immunol. 3: 233-242. [Medline] T cells. J. Invest. Dermatol. 126: 25-31. [Medline]This article has been cited by other articles:
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) or anti-mIL-17 mAb (
) 1 h before i.p. challenge with 1 x 108 CFU of E. coli. A, Absolute number of neutrophils (Gr-1 positive) in the peritoneal exudates at 24 h after E. coli infection was measured by flow cytometry. B, Bacterial numbers in the peritoneal cavity and liver at 24 h after infection. Data are the means ± SD of three to six mice for each group; *, p < 0.05; **, p < 0.01. Data are representative of three independent experiments.
