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Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses¹

Teresa M. Wozniak^*, Anthony A. Ryan^* and Warwick J. Britton^2,*,

^* Mycobacterial Research Group, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia; and Department of Medicine, Central Clinical School, University of Sydney, New South Wales, Australia

Host control of Mycobacterium tuberculosis is dependent on the activation of CD4⁺ T cells secreting IFN- and their recruitment to the site of infection. The development of more efficient vaccines against tuberculosis requires detailed understanding of the induction and maintenance of T cell immunity. Cytokines important for the development of cell-mediated immunity include IL-12 and IL-23, which share the p40 subunit and the IL-12R1 signaling chain. To explore the differential effect of IL-12 and IL-23 during M. tuberculosis infection, we used plasmids expressing IL-23 (p2AIL-23) or IL-12 (p2AIL-12) alone in dendritic cells or macrophages from IL-12p40^–/– mice. In the absence of the IL-12/IL-23 axis, immunization with a DNA vaccine expressing the M. tuberculosis Ag85B induced a limited Ag-specific T cell response and no control of M. tuberculosis infection. Codelivery of p2AIL-23 or p2AIL-12 with DNA85B induced strong proliferative and IFN--secreting T cell responses equivalent to those observed in wild-type mice immunized with DNA85B. This response resulted in partial protection against aerosol M. tuberculosis; however, the protective effect was less than in wild-type mice owing to the requirement for IL-12 or IL-23 for the optimal expansion of IFN--secreting T cells. Interestingly, bacillus Calmette-Guérin immune T cells generated in the absence of IL-12 or IL-23 were deficient in IFN- production, but exhibited a robust IL-17 secretion associated with a degree of protection against pulmonary infection. Therefore, exogenous IL-23 can complement IL-12 deficiency for the initial expansion of Ag-specific T cells and is not essential for the development of potentially protective IL-17-secreting T cells.

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 the National Health and Medical Research Council of Australia and the New South Wales Department of Health through its research infrastructure grant to the Centenary Institute of Cancer Medicine and Cell Biology.

² Address correspondence and reprint requests to Dr. Warwick J Britton, Centenary Institute of Cancer Medicine and Cell Biology, Mycobacterial Research Laboratory, Locked Bag Number 6, Newtown, NSW, Australia. E-mail address: wbritton{at}med.usyd.edu.au

³ Abbreviations used in this paper: DC, dendritic cell; BCG, bacillus Calmette-Guérin; BMDC, bone marrow-derived DC; MLN, mediastinal lymph node.

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