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* Department of Microbiology and Immunology,
Department of Medicine, and
Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461; and
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
The attenuated strain of Mycobacterium bovis known as bacille Calmette-Guérin (BCG) has been widely used as a vaccine for prevention of disease by Mycobacterium tuberculosis, but with relatively little evidence of success. Recent studies suggest that the failure of BCG may be due to its retention of immune evasion mechanisms that delay or prevent the priming of robust protective cell-mediated immunity. In this study, we describe an approach to enhance the immunogenicity of BCG by incorporating glycolipid activators of CD1d-restricted NKT cells, a conserved T cell subset with the potential to augment many types of immune responses. A method was developed for stably incorporating two forms of the NKT cell activator 
-galactosylceramide into live BCG organisms, and the impact of this on stimulation of T cell responses and protective antimycobacterial immunity was evaluated. We found that live BCG containing relatively small amounts of incorporated -galactosylceramide retained the ability to robustly activate NKT cells. Compared with immunization with unmodified BCG, the glycolipid-modified BCG stimulated increased maturation of dendritic cells and markedly augmented the priming of Ag-specific CD8+ T cells responses. These effects were correlated with improved protective effects of vaccination in mice challenged with virulent M. tuberculosis. These results support the view that mycobacteria possess mechanisms to avoid stimulation of CD8+ T cell responses and that such responses contribute significantly to protective immunity against these pathogens. Our findings raise the possibility of a simple modification of BCG that could yield a more effective vaccine for control of tuberculosis.
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 National Institutes of Health/National Institute of Allergy and Infectious Disease Grants AI45889 (to S.A.P.) and AI063537 (P01 to S.A.P., W.R.J., and J.C.). Core resources that facilitated flow cytometry and histopathology studies were supported by the Einstein Center for AIDS Research (Grant AI 051519) and the Einstein Cancer Center (Grant CA 13330). S.A.P. and W.R.J. were also supported by funding from the Aeras Global TB Vaccine Foundation and the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation. G.S.B. acknowledges support from a Personal Research Chair from James Bardrick, a Royal Society Wolfson Research Merit Award, a former Lister Institute-Jenner Research Fellowship, the Medical Research Council, and The Wellcome Trust (Grant 084923/B/08/Z).
2 Address correspondence and reprint requests to Dr. Steven A. Porcelli, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461. E-mail address: porcelli{at}aecom.yu.edu
3 Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; DC, dendritic cell; iNKT, invariant NKT; GalCer, -galactosylceramide; -C-GalCer, -C-galactosylceramide; BMDC, bone marrow-derived DC; MOI, multiplicity of infection; Treg, regulatory T cell.
4 The online version of this article contains supplemental material.
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