title: CD4+ T lymphocytes mediate in vivo clearance of plasmid DNA vaccine antigen expression and potentiate CD8+ T-cell immune responses.
abstract: There is evidence that the limited immunogenicity of plasmid DNA vaccines is the result, at least in part, of the rapid clearance of vaccine antigen expression by antigen-specific immune responses. However, the cell types responsible for the clearance of plasmid DNA vaccine antigens are not known. Here we demonstrate that macrophages, NK cells, and CD8(+) T cells did not significantly contribute to the DNA antigen clearance but CD4(+) T cells played the crucial role in attenuating plasmid DNA vaccine antigen expression. Adoptive transfer experiments demonstrate that CD4(+) T cells facilitated DNA vaccine antigen clearance in a Fas/FasL-dependent manner. Furthermore, we show that depletion of CD4(+) T cells prevented the clearance of vaccine antigen and the appearance of a CD8(+) T-cell immune response. Inoculation of major histocompatibility complex class II KO mice with the plasmid DNA led to persistent antigen expression and abolition of a CD8(+) T-cell immune response. Importantly, the prolongation of antigen expression by disrupting the CD4(+) T-cell Fas/FasL myocytes signaling led to a 3- to 5-fold increase of antigen-specific CD8(+) T-cell responses. These data demonstrate a dominant role of CD4(+) T cell-mediated cytotoxicity in plasmid DNA vaccine antigen clearance.
authors.affiliation: Division of Viral Pathogenesis, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. rgeibenl@bidmc.harvard.edu
authors.forename: Ralf
authors.initials: R
authors.lastname: Geiben-Lynn
authors.forename: John R
authors.initials: JR
authors.lastname: Greenland
authors.forename: Kwesi
authors.initials: K
authors.lastname: Frimpong-Boateng
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics; D007111:Immunity, Cellular / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010957:Plasmids / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000235:genetics; D019014:fas Receptor / Q000235:genetics
chemical_list: D000941:Antigens; D018984:Epitopes, T-Lymphocyte; D053222:Fas Ligand Protein; D019444:Vaccines, DNA; D001613:beta 2-Microglobulin; D019014:fas Receptor; D008156:Luciferases
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