Plasmid DNA vaccine-elicited cellular immune responses limit in vivo vaccine antigen expression through Fas-mediated apoptosis.
Particularly potent cellular or humoral immune responses are needed to confer protection in animal models against such pathogens as HIV/SIV, Mycobacterium tuberculosis, and malarial parasites. Persistent, high-level vaccine Ag expression may be required for eliciting such potent and durable immune responses. Although plasmid DNA immunogens are being explored as potential vaccines for protection against these pathogens, little is known about host factors that restrict long-term plasmid DNA vaccine Ag expression in vivo. We observed rapid damping of transgene expression from a plasmid DNA immunogen in wild-type, but not in T cell-deficient mice. This damping of Ag expression was temporally associated with the emergence of Ag-specific cellular immune responses. A requirement for Fas and the appearance of apoptotic nuclei at the site of vaccine inoculation suggest that T cells induce Fas-mediated apoptosis of plasmid DNA vaccine Ag-expressing cells. These studies demonstrate that high levels of in vivo Ag expression are associated with high-frequency cellular immune responses that in turn rapidly down-regulate vaccine Ag expression in vivo. These findings argue that it may not be possible to maintain persistent, high-level production of vaccine Ag in vivo to drive persistent immune responses as long as vaccine Ag production can be limited by host immune responses.
Greenland
John R
JR
Division of Viral Pathogenesis, Harvard Medical School, Beth Israel Deaconess Medical Center, 41 Avenue Louis Pasteur, Boston, MA 02215, USA.
Geiben
Ralf
R
Ghosh
Sharmistha
S
Pastor
William A
WA
Letvin
Norman L
NL
D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D007111:Immunity, Cellular; D008288:Malaria / Q000517:prevention & control; D051379:Mice; D008817:Mice, Mutant Strains; D010957:Plasmids / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes; D014376:Tuberculosis / Q000517:prevention & control; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D000941:Antigens; D019444:Vaccines, DNA; D019014:fas Receptor