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.
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.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Michele A
MA
Kutzler
Tara M
TM
Robinson
Michael A
MA
Chattergoon
Daniel K
DK
Choo
Andrew Y
AY
Choo
Philip Y
PY
Choe
Mathura P
MP
Ramanathan
Rose
R
Parkinson
Sagar
S
Kudchodkar
Yutaka
Y
Tamura
Maninder
M
Sidhu
Vidia
V
Roopchand
J Joseph
JJ
Kim
George N
GN
Pavlakis
Barbara K
BK
Felber
Thomas A
TA
Waldmann
Jean D
JD
Boyer
David B
DB
Weiner
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D049109:Cell Proliferation; D016922:Cellular Senescence; D003001:Cloning, Molecular; D005260:Female; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010957:Plasmids; D014162:Transfection; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
D016915:AIDS Vaccines; D007252:Influenza Vaccines; D019409:Interleukin-15; D019444:Vaccines, DNA; D007371:Interferon-gamma