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: Mingquan Zheng, Alistair J Ramsay, Myles B Robichaux, Corrine Kliment, Christopher Crowe, Rekha R Rapaka, Chad Steele, Florencia McAllister, Judd E Shellito, Luis Marrero, Paul Schwarzenberger, Qiu Zhong, Jay K Kolls
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 12 Pg. 3536-44 (Dec 2005) ISSN: 0021-9738 [Print] United States
• PMID: 16308571 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Adenoviridae (genetics)
• Animals
• Antigens (chemistry)
• Antigens, CD19 (biosynthesis, immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD40 Ligand (chemistry)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cancer Vaccines (metabolism)
• DNA (chemistry, 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, 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