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Inflammation
Published in: Inflammation 3/2008

01-06-2008

IL-17 Producing γδ T Cells are Required for a Controlled Inflammatory Response after Bleomycin-induced Lung Injury

Authors: Ruedi K. Braun, Christina Ferrick, Paul Neubauer, Michael Sjoding, Anja Sterner-Kock, Martin Kock, Lei Putney, David A. Ferrick, Dallas M. Hyde, Robert B. Love

Published in: Inflammation | Issue 3/2008

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Background

γδ T cells play a key role in the regulation of inflammatory responses in epithelial tissue, and in adaptive immunity, as γδ T cell deficient mice have a severely impaired capacity to clear lung pathogens. γδ T cells regulate the initial inflammatory response to microbial invasion and thereby protect against tissue injury. Here we examined the response of γδ T cells to lung injury induced by bleomycin, in an effort to study the inflammatory response in the absence of any adaptive immune response to a pathogen.

Results

After lung injury by bleomycin, we localized the γδ T cells to the lung lesions. γδ T cells were the predominant source of IL-17 (as detected by flow cytometry and real-time PCR). Moreover, γδ T cell knockout mice showed a significant reduction in cellular infiltration into the airways, reduced expression of IL-6 in the lung, and a significant delay in epithelial repair.

Conclusion

Mouse γδ T cells produce IL-17 in response to lung injury and are required for an organized inflammatory response and epithelial repair. The lack of γδ T cells correlates with increased inflammation and fibrosis.
Literature
1.
Langhorne, J., P. Mombaerts, and S. Tonegawa. 1995. alpha beta and gamma delta T cells in the immune response to the erythrocytic stages of malaria in mice. Int. Immunol. 7:1005–1011.PubMedCrossRef
2.
Mombaerts, P., J. Arnoldi, F. Russ, S. Tonegawa, and S. H. Kaufmann. 1993. Different roles of alpha beta and gamma delta T cells in immunity against an intracellular bacterial pathogen. Nature 365:53–56.PubMedCrossRef
3.
Korn, T., M. Oukka, and E. Bettelli. 2007. Th17 cells: effector T cells with inflammatory properties. Semin. Immunol. 19:362–371.
4.
Park, H., Z. Li, X. O. Yang, S. H. Chang, R. Nurieva, Y. H. Wang, Y. Wang, L. Hood, Z. Zhu, Q. Tian, and C. Dong. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6:1133–1141.PubMedCrossRef
5.
Roark, C. L., J. D. French, M. A. Taylor, A. M. Bendele, W. K. Born, and R. L. O’Brien. 2007. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. J. Immunol. 179:5576–5583.PubMed
6.
Lockhart, E., A. M. Green, and J. L. Flynn. 2006. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J. Immunol. 177:4662–4669.PubMed
7.
Kelly, M. N., J. K. Kolls, K. Happel, J. D. Schwartzman, P. Schwarzenberger, C. Combe, M. Moretto, and I. A. Khan. 2005. Interleukin-17/interleukin-17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infect. Immun. 73:617–621.PubMedCrossRef
8.
Ye, P., P. B. Garvey, P. Zhang, S. Nelson, G. Bagby, W. R. Summer, P. Schwarzenberger, J. E. Shellito, and J. K. Kolls. 2001. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am. J. Respir. Cell Mol. Biol. 25:335–340.PubMed
9.
Huang, W., L. Na, P. L. Fidel, and P. Schwarzenberger. 2004. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J. Infect. Dis. 190:624–631.PubMedCrossRef
10.
Ye, P., F. H. Rodriguez, S. Kanaly, K. L. Stocking, J. Schurr, P. Schwarzenberger, P. Oliver, W. Huang, P. Zhang, J. Zhang, J. E. Shellito, G. J. Bagby, S. Nelson, K. Charrier, J. J. Peschon, and J. K. Kolls. 2001. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194:519–527.PubMedCrossRef
11.
Langrish, C. L., Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201:233–240.PubMedCrossRef
12.
Bi, Y., G. Liu, and R. Yang. 2007. Th17 cell induction and immune regulatory effects. J. Cell. Physiol. 211:273–278.PubMedCrossRef
13.
Born, W. K., C. L. Reardon, and R. L. O’Brien. 2006. The function of gammadelta T cells in innate immunity. Curr. Opin. Immunol. 18:31–38.PubMedCrossRef
14.
Nanno, M., T. Shiohara, H. Yamamoto, K. Kawakami, and H. Ishikawa. 2007. gammadelta T cells: firefighters or fire boosters in the front lines of inflammatory responses. Immunol. Rev. 215:103–113.PubMedCrossRef
15.
Moore, T. A., B. B. Moore, M. W. Newstead, and T. J. Standiford. 2000. Gamma delta-T cells are critical for survival and early proinflammatory cytokine gene expression during murine Klebsiella pneumonia. J. Immunol. 165:2643–2650.PubMed
16.
Takano, M., H. Nishimura, Y. Kimura, Y. Mokuno, J. Washizu, S. Itohara, Y. Nimura, and Y. Yoshikai. 1998. Protective roles of gamma delta T cells and interleukin-15 in Escherichia coli infection in mice. Infect. Immun. 66:3270–3278.PubMed
17.
Nakamura, T., G. Matsuzaki, and K. Nomoto. 1999. The protective role of T-cell receptor Vgamma1+ T cells in primary infection with Listeria monocytogenes. Immunology 96:29–34.PubMedCrossRef
18.
Blum, R. H., S. K. Carter, and K. Agre. 1973. A clinical review of bleomycin–a new antineoplastic agent. Cancer 31:903–914.PubMedCrossRef
19.
Jones, A. W. 1978. Bleomycin lung damage: the pathology and nature of the lesion. Br. J. Dis. Chest 72:321–326.PubMedCrossRef
20.
Braun, R. K., A. Sterner-Kock, P. J. Kilshaw, D. A. Ferrick, and S. N. Giri. 1996. Integrin alpha E beta 7 expression on BAL CD4+, CD8+, and gamma delta T-cells in bleomycin-induced lung fibrosis in mouse. Eur. Respir. J. 9:673–679.PubMedCrossRef
21.
Thrall, R. S., and R. W. Barton. 1984. A comparison of lymphocyte populations in lung tissue and in bronchoalveolar lavage fluid of rats at various times during the development of bleomycin-induced pulmonary fibrosis. Am. Rev. Respir. Dis. 129:279–283.PubMed
22.
Zhu, J., D. A. Cohen, S. N. Goud, and A. M. Kaplan. 1996. Contribution of T lymphocytes to the development of bleomycin-induced pulmonary fibrosis. Ann. N.Y. Acad. Sci. 796:194–202.PubMedCrossRef
23.
Raisfeld, I. H. 1980. Pulmonary toxicity of bleomycin analogs. Toxicol. Appl. Pharmacol. 56:326–336.PubMedCrossRef
24.
Creemers, L. B., D. C. Jansen, A. Veen-Reurings, B. T. van den, and V. Everts. 1997. Microassay for the assessment of low levels of hydroxyproline. Biotechniques 22:656–658.PubMed
25.
Bolender, R. P., D. M. Hyde, and R. T. Dehoff. 1993. Lung morphometry: a new generation of tools and experiments for organ, tissue, cell, and molecular biology. Am. J. Physiol. 265:L521–L548.PubMed
26.
Hyde, D. M., D. J. Magliano, E. Reus, N. K. Tyler, S. Nichols, and W. S. Tyler. 1992. Computer-assisted morphometry: point, intersection, and profile counting and three-dimensional reconstruction. Microsc. Res. Tech. 21:262–270.PubMedCrossRef
27.
Yang, H., P. A. Antony, B. E. Wildhaber, and D. H. Teitelbaum. 2004. Intestinal intraepithelial lymphocyte gammadelta-T cell-derived keratinocyte growth factor modulates epithelial growth in the mouse. J. Immunol. 172:4151–4158.PubMed
28.
D’Souza, C. D., A. M. Cooper, A. A. Frank, R. J. Mazzaccaro, B. R. Bloom, and I. M. Orme. 1997. An anti-inflammatory role for gamma delta T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J. Immunol. 158:1217–1221.PubMed
29.
King, D. P., D. M. Hyde, K. A. Jackson, D. M. Novosad, T. N. Ellis, L. Putney, M. Y. Stovall, L. S. Van Winkle, B. L. Beaman, and D. A. Ferrick. 1999. Cutting edge: protective response to pulmonary injury requires gamma delta T lymphocytes. J. Immunol. 162:5033–5036.PubMed
30.
Afzali, B., G. Lombardi, R. I. Lechler, and G. M. Lord. 2007. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin. Exp. Immunol. 148:32–46.PubMedCrossRef
31.
Shin, H. C., N. Benbernou, S. Esnault, and M. Guenounou. 1999. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine 11:257–266.PubMedCrossRef
32.
Shibata, K., H. Yamada, H. Hara, K. Kishihara, and Y. Yoshikai. 2007. Resident Vdelta1+ gammadelta T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J. Immunol. 178:4466–4472.PubMed
33.
Ferrick, D. A., D. P. King, K. A. Jackson, R. K. Braun, S. Tam, D. M. Hyde, and B. L. Beaman. 2000. Intraepithelial gamma delta T lymphocytes: sentinel cells at mucosal barriers. Springer Semin. Immunopathol 22:283–296.PubMedCrossRef
34.
Tam, S., D. P. King, and B. L. Beaman. 2001. Increase of {gamma}{delta} T Lymphocytes in murine lungs occurs during recovery from pulmonary infection by nocardia asteroides. Infect. Immun. 69:6165–6171.PubMedCrossRef
35.
Hsieh, B., M. D. Schrenzel, T. Mulvania, H. D. Lepper, L. DiMolfetto-Landon, and D. A. Ferrick. 1996. In vivo cytokine production in murine listeriosis. Evidence for immunoregulation by gamma delta+ T cells. J. Immunol. 156:232–237.PubMed
36.
McKenzie, B. S., R. A. Kastelein, and D. J. Cua. 2005. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 27:17–23.PubMedCrossRef
37.
Bowman, E. P., A. A. Chackerian, and D. J. Cua. 2006. Rationale and safety of anti-interleukin-23 and anti-interleukin-17A therapy. Curr. Opin. Infect. Dis. 19:245–252.PubMedCrossRef
38.
Rohn, T. A., G. T. Jennings, M. Hernandez, P. Grest, M. Beck, Y. Zou, M. Kopf, and M. F. Bachmann. 2006. Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis. Eur. J. Immunol. 36:2857–2867.PubMedCrossRef
39.
Schrier, D. J., S. H. Phan, and P. A. Ward. 1982. Cellular sensitivity to collagen in bleomycin-treated rats. J. Immunol. 129:2156–2159.PubMed
40.
Kravis, T. C., A. Ahmed, T. E. Brown, J. D. Fulmer, and R. G. Crystal. 1976. Pathogenic mechanisms in pulmonary fibrosis: collagen-induced migration inhibition factor production and cytotoxicity mediated by lymphocytes. J. Clin. Invest. 58:1223–1232.PubMedCrossRef
41.
Nakos, G., A. Adams, and N. Andriopoulos. 1993. Antibodies to collagen in patients with idiopathic pulmonary fibrosis. Chest 103:1051–1058.PubMedCrossRef
42.
Collard, H. R., B. B. Moore, K. R. Flaherty, K. K. Brown, R. J. Kaner, T. E. King Jr., J. A. Lasky, J. E. Loyd, I. Noth, M. A. Olman, G. Raghu, J. Roman, J. H. Ryu, D. A. Zisman, G. W. Hunninghake, T. V. Colby, J. J. Egan, D. M. Hansell, T. Johkoh, N. Kaminski, D. S. Kim, Y. Kondoh, D. A. Lynch, J. Muller-Quernheim, J. L. Myers, A. G. Nicholson, M. Selman, G. B. Toews, A. U. Wells, and F. J. Martinez. 2007. Acute exacerbations of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 176:636–643.PubMedCrossRef
43.
44.
Ghosh, S., T. Mendoza, L. A. Ortiz, G. W. Hoyle, C. D. Fermin, A. R. Brody, M. Friedman, and G. F. Morris. 2002. Bleomycin sensitivity of mice expressing dominant-negative p53 in the lung epithelium. Am. J. Respir. Crit. Care Med. 166:890–897.PubMedCrossRef
45.
Serrano-Mollar, A., M. Nacher, G. Gay-Jordi, D. Closa, A. Xaubet, and O. Bulbena. 2007. Intratracheal transplantation of alveolar Type II cells reverse bleomycin-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 176:1261–1268.
46.
Watanabe, M., M. Ebina, F. M. Orson, A. Nakamura, K. Kubota, D. Koinuma, K. Akiyama, M. Maemondo, S. Okouchi, M. Tahara, K. Matsumoto, T. Nakamura, and T. Nukiwa. 2005. Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis. Mol. Ther. 12:58–67.PubMedCrossRef
47.
Yi, E. S., S. T. Williams, H. Lee, D. M. Malicki, E. M. Chin, S. Yin, J. Tarpley, and T. R. Ulich. 1996. Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality. Am. J. Pathol. 149:1963–1970.PubMed
48.
Jameson, J., and W. L. Havran. 2007. Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol. Rev. 215:114–122.PubMedCrossRef
49.
Chen, Y., K. Chou, E. Fuchs, W. L. Havran, and R. Boismenu. 2002. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc. Natl. Acad. Sci. U. S. A. 99:14338–14343.PubMedCrossRef
50.
Koohsari, H., M. Tamaoka, H. R. Campbell, and J. G. Martin. 2007. The role of gamma delta T cells in airway epithelial injury and bronchial responsiveness after chlorine gas exposure in mice. Respir. Res. 8:21.PubMedCrossRef
51.
Inoue, D., M. Numasaki, M. Watanabe, H. Kubo, T. Sasaki, H. Yasuda, M. Yamaya, and H. Sasaki. 2006. IL-17A promotes the growth of airway epithelial cells through ERK-dependent signaling pathway. Biochem. Biophys. Res. Commun. 347:852–858.PubMedCrossRef
52.
Manoury, B., S. Nenan, I. Guenon, V. Lagente, and E. Boichot. 2007. Influence of early neutrophil depletion on MMPs/TIMP-1 balance in bleomycin-induced lung fibrosis. Int. Immunopharmacol. 7:900–911.PubMedCrossRef
53.
Kolls, J. K., and A. Linden. 2004. Interleukin-17 family members and inflammation. Immunity. 21:467–476.PubMedCrossRef
54.
Hyde, D. M., L. A. Miller, R. J. McDonald, M. Y. Stovall, V. Wong, K. E. Pinkerton, C. D. Wegner, R. Rothlein, and C. G. Plopper. 1999. Neutrophils enhance clearance of necrotic epithelial cells in ozone-induced lung injury in rhesus monkeys. Am. J. Physiol. 277:L1190–L1198.PubMed
55.
Liu, W., A. L. Putnam, Z. Xu-Yu, G. L. Szot, M. R. Lee, S. Zhu, P. A. Gottlieb, P. Kapranov, T. R. Gingeras, B. F. de St Groth, C. Clayberger, D. M. Soper, S. F. Ziegler, and J. A. Bluestone. 2006. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4(+) T reg cells. J. Exp. Med. 203:1701–1711.PubMedCrossRef
56.
Gunnarsson, M., S. M. Walther, T. Seidal, G. D. Bloom, and S. Lennquist. 1998. Exposure to chlorine gas: effects on pulmonary function and morphology in anaesthetised and mechanically ventilated pigs. J. Appl. Toxicol. 18:249–255.PubMedCrossRef
57.
Crouch, E. 1990. Pathobiology of pulmonary fibrosis. Am. J. Physiol. 259:159–184.
58.
Eickelberg, O., A. Pansky, R. Mussmann, M. Bihl, M. Tamm, P. Hildebrand, A. P. Perruchoud, and M. Roth. 1999. Transforming growth factor-beta1 induces interleukin-6 expression via activating protein-1 consisting of JunD homodimers in primary human lung fibroblasts. J. Biol. Chem. 274:12933–12938.PubMedCrossRef
59.
Xing, Z., J. Gauldie, G. Cox, H. Baumann, M. Jordana, X. F. Lei, and M. K. Achong. 1998. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J. Clin. Invest. 101:311–320.PubMedCrossRef
60.
Gurujeyalakshmi, G., Y. Wang, and S. N. Giri. 2000. Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kappaB in mice. J. Pharmacol. Exp. Ther. 293:82–90.PubMed
61.
Tabata, C., Y. Kadokawa, R. Tabata, M. Takahashi, K. Okoshi, Y. Sakai, M. Mishima, and H. Kubo. 2006. All-trans-retinoic acid prevents radiation- or bleomycin-induced pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 174:1352–1360.PubMedCrossRef
62.
Sener, G., N. Topaloglu, A. O. Sehirli, F. Ercan, and N. Gedik. 2007. Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm. Pharmacol. Ther. 20:642–649.PubMedCrossRef
63.
Tabata, C., R. Tabata, Y. Kadokawa, S. Hisamori, M. Takahashi, M. Mishima, T. Nakano, and H. Kubo. 2007. Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice. J. Immunol. 179:708–714.PubMed
Metadata
Title
IL-17 Producing γδ T Cells are Required for a Controlled Inflammatory Response after Bleomycin-induced Lung Injury
Authors
Ruedi K. Braun
Christina Ferrick
Paul Neubauer
Michael Sjoding
Anja Sterner-Kock
Martin Kock
Lei Putney
David A. Ferrick
Dallas M. Hyde
Robert B. Love
Publication date
01-06-2008
Publisher
Springer US
Published in
Inflammation / Issue 3/2008
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-008-9062-6

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