Effects of DNA- and Mycobacterium bovis BCG-based delivery of the Flt3 ligand on protective immunity to Mycobacterium tuberculosis.
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-gamma) 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-gamma-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.
Triccas
James A
JA
Microbial Pathogenesis and Immunity Group, Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, Australia. jamiet@infdis.usyd.edu.au
Shklovskaya
Elena
E
Spratt
Joanne
J
Ryan
Anthony A
AA
Palendira
Umaimainthan
U
Fazekas de St Groth
Barbara
B
Britton
Warwick J
WJ
D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D015169:Colony Count, Microbial; D003713:Dendritic Cells / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology
D000942:Antigens, Bacterial; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; C084881:flt3 ligand protein; D007371:Interferon-gamma