Coimmunization with an Optimized IL-15 Plasmid Results in Enhanced Function and Longevity of CD8 T Cells That Are Partially Independent of CD4 T Cell Help

Abstract

DNA vaccines are a promising technology for the induction of Ag-specific immune responses, and much recent attention has gone into improving their immune potency. In this study we test the feasibility of delivering a plasmid encoding IL-15 as a DNA vaccine adjuvant for the induction of improved Ag-specific CD8+ T cellular immune responses. Because native IL-15 is poorly expressed, we used PCR-based strategies to develop an optimized construct that expresses 80-fold higher than the native IL-15 construct. Using a DNA vaccination model, we determined that immunization with optimized IL-15 in combination with HIV-1gag DNA constructs resulted in a significant enhancement of Ag-specific CD8+ T cell proliferation and IFN-γ secretion, and strong induction of long-lived CD8+ T cell responses. In an influenza DNA vaccine model, coimmunization with plasmid expressing influenza A PR8/34 hemagglutinin with the optimized IL-15 plasmid generated improved long term CD8+ T cellular immunity and protected the mice against a lethal mucosal challenge with influenza virus. Because we observed that IL-15 appeared to mostly adjuvant CD8+ T cell function, we show that in the partial, but not total, absence of CD4+ T cell help, plasmid-delivered IL-15 could restore CD8 secondary immune responses to an antigenic DNA plasmid, supporting the idea that the effects of IL-15 on CD8+ T cell expansion require the presence of low levels of CD4 T cells. These data suggest a role for enhanced plasmid IL-15 as a candidate adjuvant for vaccine or immunotherapeutic studies.

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

“…Notably, the loss of IFN-␥-producing CD8 ϩ T cells specific to HIV Ags has been observed in HIV Gag DNA-immunized CD4 knockout mice. These data support the need for CD4 ϩ T cells during priming for generation of functional CD8 ϩ effector cells (38). In our study, we found that the induced CD4 ϩ T cell response in mice was below detectable level; this may explain in part the presence of a high proportion of CD8 ϩ T cells that functionally were not in the immediate IFN-␥ effector phenotype.…”

Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

“…It was reported that the effects of IL-7 as a genetic adjuvant have been known to be weaker and less effective than those of IL-15, a well-known and effective vaccine adjuvant [29]. In contrast to IL-7, nonlytic Fc fusion to IL-15 slightly increased, albeit insignificantly, the adjuvant effect of IL-15 on enhancing CD8 1 T-cell responses (Supporting Information Fig.…”

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

“…Recent advances in immunology have shown that several types of molecules may be used as novel adjuvants to enhance immunogenicity of vaccines, such as cytokines, chemokines, Toll-like receptor ligands, and some costimulatory molecules [44][45][46][47]. Among these molecules, CD40L is attractive since it is one of the main mechanisms by which CD4 + T cells provide help to CTL and B cells [16,18,19,31].…”