Targeting dendritic cells with antigen via dendritic cell-associated promoters

Abstract

The induction of tumor-specific immune responses is largely dependent on the ability of dendritic cells (DCs) to present tumor-associated antigens to T lymphocytes. Therefore, we investigated the use of DC-associated promoter-driven genetic vaccines to specifically target DC in vivo. Restricted expression of vaccine-encoding genes in DC should enhance specificity and improves their safety for clinical applications. Hereto, 3 --5 kb upstream sequences of the murine genes encoding CD11c, DC-SIGN, DC-STAMP and Langerin were isolated, characterized and subcloned into enhanced green fluorescent protein (EGFP) reporter constructs. Upon electroporation, EGFP was expressed in DC cell lines, but not in other cell lines, confirming DCrestricted promoter activity. When these promoters were cloned into a construct upstream of the gene for ovalbumin (OVA), it appeared that DC-STAMP promoter-driven expression of OVA (pDCSTAMP/OVA) in DC yielded the most efficient OVA-specific CD4 þ and CD8 þ T-cell responses in vitro. Administration of pDC-STAMP/OVA in vivo, using the tattoo gun vaccination system, evoked specific immune responses as evidenced in a mouse tumor model. Adoptively transferred pDC-STAMP/OVA-transfected DCs induced strong CD8 þ T-cell proliferation in vivo. These experiments demonstrate that our DC-directed promoter constructs are potential tools to restrict antigen expression in DC and could be implemented to modulate DC function by the introduction of relevant proteins.

Monocyte-Derived Dendritic Cells from Patients with Dermatophytosis Restrict the Growth of Trichophyton rubrum and Induce CD4-T Cell Activation

“…DCs are the most potent APC of the immune system and are vital for the initiation of primary T cell-mediated immune responses that are the hallmark of CMI [20]. As host defense against T. rubrum requires the induction of CMI, we sought to determine a role for DCs and macrophages in this process.…”

Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

“…Thus, targeting antigens to DC-STAMP tolerize antigen specific Tcell responses in vivo. Conversely, using DC-STAMP promoter driven construct linked to OVA, resulted in strong OVA-specific CD4+ and CD8+ T-cell responses in vitro and in vivo and protected mice against OVA+ tumor challenge [203]. Thus, DC-STAMP shows promise as a target for cancer vaccine antigen targeting approach.…”

Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation

“…OVA protein is a well-established model antigen to study anti-tumor immunity [44]. Many previous studies also have used OVA as a model antigen for tumor immunotherapeutic studies [45–47]. However, future study using less immunogenic tumor antigen will be interesting.…”