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Infection and Immunity, November 2007, p. 5368-5375, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00322-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effects of DNA- and Mycobacterium bovis BCG-Based Delivery of the Flt3 Ligand on Protective Immunity to Mycobacterium tuberculosis

James A. Triccas,^1,3* Elena Shklovskaya,³ Joanne Spratt ,^3, Anthony A. Ryan,³ Umaimainthan Palendira ,^3, Barbara Fazekas de StGroth,³ and Warwick J. Britton^2,3

Microbial Pathogenesis and Immunity Group, Discipline of Infectious Diseases and Immunology,¹ Discipline of Medicine,² Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Sydney, Australia³

Received 27 February 2007/ Returned for modification 24 April 2007/ Accepted 3 August 2007

The control of intracellular pathogens such as Mycobacterium tuberculosis is dependent on the activation and maintenance of pathogen-reactive T cells. Dendritic cells (DCs) are the major antigen-presenting cells initiating antimycobacterial T-cell responses in vivo. To investigate if immunization strategies that aim to optimize DC function can improve protective immunity against virulent mycobacterial infection, we exploited the ability of the hematopoietic growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) to expand the number of DCs in vivo. A DNA fusion of the genes encoding murine Flt3L and M. tuberculosis antigen 85B stimulated enhanced gamma interferon (IFN-) release by T cells and provided better protection against virulent M. tuberculosis than DNA encoding the single components. Vaccination of mice with a recombinant Mycobacterium bovis BCG strain secreting Flt3L (BCG:Flt3L) led to early expansion of DCs compared to immunization with BCG alone, and this effect was associated with increased stimulation of BCG-reactive IFN--secreting T cells. BCG and BCG:Flt3L provided similar protective efficacies against low-dose aerosol M. tuberculosis; however, immunization of immunodeficient mice revealed that BCG:Flt3L was markedly less virulent than conventional BCG. These results demonstrate the potential of in vivo targeting of DCs to improve antimycobacterial vaccine efficacy.

Published ahead of print on 27 August 2007.

Editor: J. L. Flynn

Present address: School of Biomedical Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.

Present address: Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.