Enhanced activation of T cells by dendritic cells engineered to hyperexpress a triad of costimulatory molecules.

Abstract

BACKGROUND:

Activation and proliferation of T cells are essential for a successful cellular immune response to an antigen. Antigen-presenting cells (APCs) activate T cells through a two-signal mechanism. The first signal is antigen specific and causes T cells to enter the cell cycle. The second signal involves a costimulatory molecule that interacts with a ligand on the T-cell surface and leads to T-cell cytokine production and their proliferation. Dendritic cells express several costimulatory molecules and are believed to be the most potent APCs. Two recombinant poxvirus vectors (replication-defective avipox [fowlpox; rF] and a replication-competent vaccinia [rV]) have been engineered to express a triad of costimulatory molecules (B7-1, intercellular adhesion molecule-1, and leukocyte function-associated antigen-3; designated TRICOM). This study was designed to determine if dendritic cells infected with these vectors would have an enhanced capacity to stimulate T-cell responses.

METHODS:

Murine dendritic cells (of both intermediate maturity and full maturity) were infected with rF-TRICOM or rV-TRICOM and were used in vitro to stimulate naive T cells with the use of a pharmacologic agent as signal 1, to stimulate T cells in allospecific mixed lymphocyte cultures, and to stimulate CD8(+) T cells specific for a peptide from the ovalbumin (OVA) protein. In addition, dendritic cells infected with TRICOM vectors were pulsed with OVA peptide and used to vaccinate mice to examine T-cell responses in vivo. All statistical tests were two-sided.

RESULTS:

Dendritic cells infected with either rF-TRICOM or rV-TRICOM were found to greatly enhance naive T-cell activation (P<.001), allogeneic responses of T cells (P<.001), and peptide-specific T-cell stimulation in vitro (P<.001). Peptide-pulsed dendritic cells infected with rF-TRICOM or rV-TRICOM induced cytotoxic T-lymphocyte activity in vivo to a markedly greater extent than peptide-pulsed dendritic cells (P =.001 in both).

CONCLUSIONS:

The ability of dendritic cells to activate both naive and effector T cells in vitro and in vivo can be enhanced with the use of poxvirus vectors that potentiate the hyperexpression of a triad of costimulatory molecules. Use of either rF-TRICOM or rV-TRICOM vectors significantly improved the efficacy of dendritic cells in priming specific immune responses. These studies have implications in vaccine strategies for both cancer and infectious diseases.

• Authors: J W Hodge, A N Rad, D W Grosenbach, H Sabzevari, A G Yafal, L Gritz, J Schlom
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 92 Issue 15 Pg. 1228-39 (Aug 02 2000) ISSN: 0027-8874 [Print] United States
• PMID: 10922408 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• B7-1 Antigen
• CD40 Antigens
• CD58 Antigens
• Carcinoembryonic Antigen
• Cytokines
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Apoptosis (immunology)
• B7-1 Antigen (immunology)
• CD40 Antigens (immunology)
• CD58 Antigens (immunology)
• Carcinoembryonic Antigen (immunology)
• Cell Line
• Cytokines (immunology)
• Dendritic Cells (immunology, virology)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic
• Genetic Vectors
• Intercellular Adhesion Molecule-1 (immunology)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Poxviridae
• T-Lymphocytes (immunology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation