title: Plasmid-encoded interleukin-15 receptor alpha enhances specific immune responses induced by a DNA vaccine in vivo.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kraynyak
authors.forename: Michele A
authors.initials: MA
authors.lastname: Kutzler
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Cisper
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Laddy
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Morrow
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D051379:Mice; D010957:Plasmids / Q000235:genetics*; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D019444:Vaccines, DNA; D007371:Interferon-gamma