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

• Published in: The Journal of immunology (1950) Vol. 175; no. 1; pp. 112 - 123
• Main Authors: Kutzler, Michele A, Robinson, Tara M, Chattergoon, Michael A, Choo, Daniel K, Choo, Andrew Y, Choe, Philip Y, Ramanathan, Mathura P, Parkinson, Rose, Kudchodkar, Sagar, Tamura, Yutaka, Sidhu, Maninder, Roopchand, Vidia, Kim, J. Joseph, Pavlakis, George N, Felber, Barbara K, Waldmann, Thomas A, Boyer, Jean D, Weiner, David B
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-07-2005
• Subjects: AIDS Vaccines - genetics; AIDS Vaccines - immunology; AIDS Vaccines - pharmacology; Amino Acid Sequence; Animals; Base Sequence; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Cellular Senescence; Cloning, Molecular; Female; Genetic Vectors; HeLa Cells; Humans; Immunization; Immunologic Memory; In Vitro Techniques; Influenza Vaccines - genetics; Influenza Vaccines - immunology; Influenza Vaccines - pharmacology; Interferon-gamma - biosynthesis; Interleukin-15 - genetics; Interleukin-15 - immunology; Lymphocyte Activation; Lymphocyte Cooperation; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Plasmids; Transfection; Vaccines, DNA - genetics; Vaccines, DNA - immunology; Vaccines, DNA - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.1.112

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-gamma 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.