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*Laboratory for Infection and Immunity, Departments of Medical Microbiology and Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and
Department of Immunology, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People’s Republic of China
Although their contribution to host defense against extracellular infections has been well defined, IL-17 and Th17 are generally thought to have limited impact on intracellular infections. In this study, we investigated the role and mechanisms of IL-17/Th17 in host defense against Chlamydia muridarum, an obligate intracellular bacterium, lung infection. Our data showed rapid increase in IL-17 production and expansion of Th17 cells following C. muridarum infection and significant detrimental impact of in vivo IL-17 neutralization by anti-IL-17 mAb on disease course, immune response, and dendritic cell (DC) function. Specifically, IL-17-neutralized mice exhibited significantly greater body weight loss, higher organism growth, and much more severe pathological changes in the lung compared with sham-treated control mice. Immunological analysis showed that IL-17 neutralization significantly reduced Chlamydia-specific Th1 responses, but increased Th2 responses. Interestingly, the DC isolated from IL-17-neutralized mice showed lower CD40 and MHC II expression and IL-12 production, but higher IL-10 production compared with those from sham-treated mice. In two DC-T cell coculture systems, DC isolated from IL-17-neutralized mice induced higher IL-4, but lower IFN-
production by Ag-specific T cells than those from sham-treated mice in cell priming and reaction settings. Adoptive transfer of DC isolated from IL-17-neutralized mice, unlike those from sham-treated mice, failed to protect the recipients against challenge infection. These findings provide in vivo evidence that IL-17/Th17 plays an important role in host defense against intracellular bacterial infection, and suggest that IL-17/Th17 can promote type 1 T cell immunity through modulating DC function.
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 was supported by grants (to X.Y.) from Canadian Institutes of Health Research, Manitoba Health Research Council, and Manitoba Institute of Child Health, and a grant (to H.B.) from Tianjin Municipal Science and Technology Commission (07JCYBJC10600). X.G. is a trainee in Canadian Institutes of Health Research National Training Program in Allergy/Asthma and a holder of Manitoba Institute of Child Health Studentship. A.G.J. was a trainee in the Canadian Institutes of Health Research/International Centre for Infectious Diseases National Training Program in Infectious Diseases and a holder of Manitoba Health Research Council postdoctoral fellowship. X.Y. is the Canada Research Chair in Infection and Immunity.
2 Address correspondence and reprint requests to Dr. Xi Yang, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Room 523, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 0W3. E-mail address: yangxi{at}cc.umanitoba.ca
3 Abbreviations used in this paper: KO, gene knockout; BAL, bronchoalveolar lavage; BM, bone marrow; BMDC, BM-derived dendritic cell; Cm, Chlamydia muridarum; DC, dendritic cell; EB, elementary body; IFU, inclusion-forming unit; LN, lymph node; p.i., postinfection; rmIL, murine rIL.
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