Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases.
Apoptotic bodies can be used to target delivery of DNA-expressed immunogens into professional antigen-presenting cells (APCs). Here we show that antigen-laden apoptotic bodies created by vectors co-expressing influenza virus hemagglutinin (HA) or nucleoprotein (NP) genes and mutant caspase genes markedly increased T-cell responses. Both CD8 and CD4 T-cell responses were affected. The adjuvant activity was restricted to partially inactivated caspases that allowed immunogen expression before the generation of apoptotic bodies. Active-site mutants of murine caspase 2 and an autocatalytic chimera of murine caspase 2 prodomain and human caspase 3 induced apoptosis that did not interfere with immunogen expression. The adjuvant activity also enhanced B-cell responses, but to a lesser extent than T-cell responses. The large increases in T-cell responses represent one of the strongest effects to date of a DNA adjuvant on cellular immunity.
Sasaki
S
S
Division of Microbiology and Immunology, Yerkes Regional Primate Research Center of Emory University, Atlanta, GA 30329, USA.
Amara
R R
RR
Oran
A E
AE
Smith
J M
JM
Robinson
H L
HL
D016475:3T3 Cells; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D000938:Antigen-Presenting Cells; D017209:Apoptosis; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D020169:Caspases / Q000235:genetics* / Q000276:immunology*; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins; D006388:Hemagglutinins / Q000096:biosynthesis; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009698:Nucleoproteins / Q000096:biosynthesis; D009975:Orthomyxoviridae / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D017304:Annexin A5; D006388:Hemagglutinins; D008164:Luminescent Proteins; D009698:Nucleoproteins; D049452:Green Fluorescent Proteins; D004247:DNA; D020169:Caspases