Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases
Shin Sasaki1, 2, Rama R. Amara1, Alp E. Oran1, James M. Smith1
& Harriet L. Robinson1
1
Division of Microbiology and Immunology, Yerkes Regional Primate Research Center of Emory University, Atlanta, GA 30329.
2
Current address: Department of Bioregulation, Leprosy Research Center, National Institute of Infectious Diseases, 4-2*1 Aoba-cho, Tokyo, 182-0002, Japan.
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.
