Emerging evidence supports the concept that T helper type 17 (TH17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the TH17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony–stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the TH17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.
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Gene Expression Omnibus
Weaver, C.T., Hatton, R.D., Mangan, P.R. & Harrington, L.E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).
Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).
Lubberts, E. The role of IL-17 and family members in the pathogenesis of arthritis. Curr. Opin. Investig. Drugs 4, 572–577 (2003).
Harrington, L.E. et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17–producing T cells. Immunity 24, 179–189 (2006).
Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Wilson, N.J. et al. Development, cytokine profile and function of human interleukin 17–producing helper T cells. Nat. Immunol. 8, 950–957 (2007).
Acosta-Rodriguez, E.V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
Happel, K.I. et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005).
Toy, D. et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 177, 36–39 (2006).
Ye, P. et al. 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, 519–528 (2001).
Chung, D.R. et al. CD4+ T cells mediate abscess formation in intra-abdominal sepsis by an IL-17–dependent mechanism. J. Immunol. 170, 1958–1963 (2003).
Higgins, S.C., Jarnicki, A.G., Lavelle, E.C. & Mills, K.H. TLR4 mediates vaccine-induced protective cellular immunity to Bordetella pertussis: role of IL-17–producing T cells. J. Immunol. 177, 7980–7989 (2006).
Wu, Q. et al. IL-23–dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection. Microbes Infect. 9, 78–86 (2007).
Dumoutier, L., Louahed, J. & Renauld, J.C. Cloning and characterization of IL-10–related T cell–derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J. Immunol. 164, 1814–1819 (2000).
Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).
Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by TH17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).
Khader, S.A. et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-γ responses if IL-12p70 is available. J. Immunol. 175, 788–795 (2005).
Zenewicz, L.A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).
Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).
Khader, S.A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).
Berger, T. et al. Lipocalin 2–deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 103, 1834–1839 (2006).
Flo, T.H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Chakinala, M.M. & Trulock, E.P. Pneumonia in the solid organ transplant patient. Clin. Chest Med. 26, 113–121 (2005).
McAllister, F. et al. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-α and granulocyte colony–stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J. Immunol. 175, 404–412 (2005).
Huang, W., Na, L., Fidel, P.L. & Schwarzenberger, P. Requirement of interleukin-17A for systemic anti–Candida albicans host defense in mice. J. Infect. Dis. 190, 624–631 (2004).
Shibata, K., Yamada, H., Hara, H., Kishihara, K. & Yoshikai, Y. Resident Vδ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J. Immunol. 178, 4466–4472 (2007).
Kao, C.Y. et al. IL-17 markedly up-regulates β-defensin-2 expression in human airway epithelium via JAK and NF-κB signaling pathways. J. Immunol. 173, 3482–3491 (2004).
Singh, P.K. et al. Production of β-defensins by human airway epithelia. Proc. Natl. Acad. Sci. USA 95, 14961–14966 (1998).
Malley, R. et al. Antibody-independent, interleukin-17A–mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide. Infect. Immun. 74, 2187–2195 (2006).
Langrish, C.L. et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96–105 (2004).
Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).
Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells. Nat. Immunol. 7, 929–936 (2006).
You, Y., Richer, E.J., Huang, T. & Brody, S.L. Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. Am. J. Physiol. Lung Cell. Mol. Physiol. 283, L1315–L1321 (2002).
Taswell, C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J. Immunol. 126, 1614–1619 (1981).
Franks, T.J. et al. Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore. Hum. Pathol. 34, 743–748 (2003).
Fallert, B.A. & Reinhart, T.A. Improved detection of simian immunodeficiency virus RNA by in situ hybridization in fixed tissue sections: combined effects of temperatures for tissue fixation and probe hybridization. J. Virol. Methods 99, 23–32 (2002).
The authors would like to acknowledge support from the following Public Health Service grants: 5R01HL079142 (J.K.K.), P50HL084932, and P30DK072506 (J.K.K. and J.M.P.). We would like to thank Y. Iwakura (Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo) for the Il17a−/− mice, and T. Mak (University Health Network, Toronto) for the Lcn2−/− mice.
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Aujla, S., Chan, Y., Zheng, M. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14, 275–281 (2008). https://doi.org/10.1038/nm1710
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