Plasmid-encoded DNA vaccines appear to be a safe and effective method for delivering antigen; however, the immunogenicity of such vaccines is often suboptimal. Cytokine adjuvants including interleukin (IL)-12, RANTES, granulocyte-macrophage colony-stimulating factor, IL-15, and others have been used to augment the immune response against DNA vaccines. In particular, IL-15 binds to a unique high-affinity receptor, IL-15R alpha; is trans-presented to CD8(+) T cells expressing the common betagamma chain; and has been shown to play a role in the generation, maintenance, and proliferation of antigen-specific CD8(+) T cells. In this study, we took the unique approach of using both a cytokine and its receptor as an adjuvant in an HIV-1 vaccine strategy. To study IL-15R alpha expression, a unique monoclonal antibody (KK1.23) was generated to confirm receptor expression in vitro. Coimmunization of IL-15 and IL-15R alpha plasmids with HIV-1 antigenic plasmids in mice enhanced the antigen-specific immune response 2-fold over IL-15 immunoadjuvant alone. Furthermore, plasmid-encoded IL-15R alpha augments immune responses in the absence of IL-15, suggesting its role as a novel adjuvant. Moreover, pIL-15R alpha enhanced the cellular, but not the humoral, immune response as measured by antigen-specific IgG antibody. This is the first report describing that IL-15R alpha itself can act as an adjuvant by enhancing an antigen-specific T cell response. Uniquely, pIL-15 and pIL-15R alpha adjuvants combined, but not the receptor alpha chain alone, may be useful as a strategy for generating and maintaining memory CD8(+) T cells in a DNA vaccine.