CD4+ T Cell-Independent DNA Vaccination Against Opportunistic Infections

J Clin Invest. 2005 Dec;115(12):3536-44. doi: 10.1172/JCI26306. Epub 2005 Nov 23.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antigens / chemistry
  • Antigens, CD19 / biosynthesis
  • Antigens, CD19 / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Ligand / chemistry
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / metabolism
  • DNA / chemistry
  • DNA / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Haplorhini
  • Immunoglobulin G / chemistry
  • Immunoprecipitation
  • Interferon-gamma / metabolism
  • Major Histocompatibility Complex
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Microscopy, Fluorescence
  • Models, Genetic
  • Opportunistic Infections / immunology
  • Opportunistic Infections / therapy*
  • Plasmids / metabolism
  • Pneumonia, Pneumocystis / metabolism
  • Proprotein Convertases / metabolism
  • Protein Structure, Tertiary
  • Proteomics / methods
  • RNA / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism
  • Spleen / cytology
  • T-Lymphocytes / immunology
  • Time Factors
  • Vaccines, DNA*

Substances

  • Antigens
  • Antigens, CD19
  • Cancer Vaccines
  • Immunoglobulin G
  • Saccharomyces cerevisiae Proteins
  • Vaccines, DNA
  • CD40 Ligand
  • RNA
  • Interferon-gamma
  • DNA
  • Proprotein Convertases
  • KEX2 protein, S cerevisiae