title: CD4+ T cell-independent DNA vaccination against opportunistic infections.
abstract: Depletion or dysfunction of CD4+ T lymphocytes profoundly perturbs host defenses and impairs immunogenicity of vaccines. Here, we show that plasmid DNA vaccination with a cassette encoding antigen (OVA) and a second cassette encoding full-length CD40 ligand (CD40L), a molecule expressed on activated CD4+ T lymphocytes and critical for T cell helper function, can elicit significant titers of antigen-specific immunoglobulins in serum and Tc1 CD8+ T cell responses in CD4-deficient mice. To investigate whether this approach leads to CD4+ T cell-independent vaccine protection against a prototypic AIDS-defining infection, Pneumocystis (PC) pneumonia, we used serum from mice vaccinated with PC-pulsed, CD40L-modified DCs to immunoprecipitate PC antigens. Kexin, a PC antigen identified by this approach, was used in a similar DNA vaccine strategy with or without CD40L. CD4-deficient mice receiving DNA vaccines encoding Kexin and CD40L showed significantly higher anti-PC IgG titers as well as opsonic killing of PC compared with those vaccinated with Kexin alone. Moreover, CD4-depleted, Kexin-vaccinated mice showed a 3-log greater protection in a PC challenge model. Adoptive transfer of CD19+ cells or IgG to SCID mice conferred protection against PC challenge, indicating a role of humoral immunity in the protection. The results of these studies show promise for CD4-independent vaccination against HIV-related or other opportunistic pathogens.
authors.affiliation: Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
authors.forename: Mingquan
authors.initials: M
authors.lastname: Zheng
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ramsay
authors.forename: Myles B
authors.initials: MB
authors.lastname: Robichaux
authors.forename: Corrine
authors.initials: C
authors.lastname: Kliment
authors.forename: Christopher
authors.initials: C
authors.lastname: Crowe
authors.forename: Rekha R
authors.initials: RR
authors.lastname: Rapaka
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Florencia
authors.initials: F
authors.lastname: McAllister
authors.forename: Judd E
authors.initials: JE
authors.lastname: Shellito
authors.forename: Luis
authors.initials: L
authors.lastname: Marrero
authors.forename: Paul
authors.initials: P
authors.lastname: Schwarzenberger
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhong
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000941:Antigens / Q000737:chemistry; D018941:Antigens, CD19 / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D000882:Haplorhini; D007074:Immunoglobulin G / Q000737:chemistry; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009894:Opportunistic Infections / Q000276:immunology / Q000628:therapy*; D010957:Plasmids / Q000378:metabolism; D011020:Pneumonia, Pneumocystis / Q000378:metabolism; D043484:Proprotein Convertases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D040901:Proteomics / Q000379:methods; D012313:RNA / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D019444:Vaccines, DNA
chemical_list: D000941:Antigens; D018941:Antigens, CD19; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D029701:Saccharomyces cerevisiae Proteins; D019444:Vaccines, DNA; D023201:CD40 Ligand; D012313:RNA; D007371:Interferon-gamma; D004247:DNA; D043484:Proprotein Convertases; C058751:KEX2 protein, S cerevisiae