Cross-Priming as a Predominant Mechanism for Inducing CD8+ T Cell Responses in Gene Gun DNA Immunization

Cho, Jaeho; Youn, Jin Won; Sung, Young Chul

doi:10.4049/jimmunol.167.10.5549

Cited by 96 publications

(85 citation statements)

References 64 publications

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“…We propose that cross-priming may play a more pronounced role in loading Ag into LC that repopulate the GI site. This interpretation is consistent with findings from Cho et al (26), who addressed the role of crosspriming without direct transfection of LC, by demonstrating the ability to activate adoptively transferred Ag-specific CD8 T cells 7 and 21 days after GI, well after the first wave of LC migrated from the GI site. Although their data provide strong evidence that crosspriming plays a predominant role in generating humoral and cellular responses when using a keratinocyte promoter-driven GI vector, they did not directly examine the transfection of migratory cells from the GI site.…”

Section: Discussionsupporting

confidence: 80%

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

Timares

Safer

et al. 2003

The Journal of Immunology

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Determining the mechanism of Ag loading of Langerhans cells (LC) for genetic immunization (GI) is complicated by the inability to distinguish between the response generated by direct transfection of LC from that due to exogenous uptake. To unravel this mechanism, we examined the impact of gene gun treatment on LC with respect to their activation and migration from skin, transgene expression, and ability to initiate humoral and cellular immune responses upon transfer to naive mice. To assess responses generated by direct LC transfection, an RU486-inducible expression system was used as a GI vector. In vitro skin organ cultures were developed from gene gun immunized mouse ear specimens to obtain LC. Gene gun treatment markedly augmented (3-fold) LC migration from ear skin, and these LC expressed the transgene at RNA and protein levels. Transfer of 2 × 105 migratory cells resulted in identical cellular responses to, but 10-fold lower humoral responses than, standard GI. Using an RU486-inducible system, we were able to measure responses generated by directly transfected LC. Our results indicate that direct transfection is a predominant pathway for LC Ag loading. The ability to regulate transgene expression with inducible DC-based vaccines demonstrates a new level of immunological control.

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Section: Discussionsupporting

confidence: 80%

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

Timares

Safer

et al. 2003

The Journal of Immunology

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“…The difference in responses generated from TRP2 human IgG1 DNA compared to the protein equivalent suggests that the direct transfection of skin APC plays a role in the generation of these immune responses. The gene gun was initially believed to stimulate CTL by direct transfection of skin APC but has more recently been shown to also induce CTL via cross presentation [36,37]. We have also shown that the FcgR is important in generating high-avidity but not high-frequency responses from the DNA vaccination.…”

Section: Discussionmentioning

confidence: 87%

DNA vaccination with T‐cell epitopes encoded within Ab molecules induces high‐avidity anti‐tumor CD8⁺ T cells

et al. 2010

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Stimulation of high-avidity CTL responses is essential for effective anti-tumor and antiviral vaccines. In this study we have demonstrated that a DNA vaccine incorporating CTL epitopes within an Ab molecule results in high-avidity T-cell responses to both foreign and self epitopes. The avidity and frequency was superior to peptide, peptide-pulsed DC vaccines or a DNA vaccine incorporating the epitope within the native Ag. The DNA Ab vaccine was superior to an identical protein vaccine that can only cross-present, indicating a role for direct presentation by the DNA vaccine. However, the avidity of CTL responses was significantly reduced in Fc receptor c knockout mice or if the Fc region was removed suggesting that cross presentation of Ag via Fc receptor was also important in the induction of high-avidity CTL. These results suggest that generation of high-avidity CTL responses by the DNA vaccine is related to its ability to both directly present and crosspresent the epitope. High-avidity responses were capable of efficient anti-tumor activity in vitro and in vivo. This study demonstrates a vaccine strategy to generate high-avidity CTL responses that can be used in anti-tumor and anti-viral vaccine settings.

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“…This is consistent with a previous report showing that the priming of CTLs using gene gun occurred through crosspriming and was independent of CD4 þ T-cell help. 42 However, the need for CD4 þ help in the priming of CTLs is still controversial, whereas recent data suggest that CD4 þ T help is needed for maintenance of a long-lived CTL response. 43 We have shown that the immunogenicity of the NS3 gene can be further improved by inclusion of NS4A.…”

Section: Codon Optimization and Rna Amplification For Hcv Ns3/4amentioning

confidence: 99%

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

et al. 2004

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We have recently shown that the NS3-based genetic immunogens should contain also hepatitis C virus (HCV) nonstructural (NS) 4A to utilize fully the immunogenicity of NS3. The next step was to try to enhance immunogenicity by modifying translation or mRNA synthesis. To enhance translation efficiency, a synthetic NS3/4A-based DNA (coNS3/4A-DNA) vaccine was generated in which the codon usage was optimized (co) for human cells. In a second approach, expression of the wild-type (wt) NS3/4A gene was enhanced by mRNA amplification using the Semliki forest virus (SFV) replicon (wtNS3/4A-SFV). Transient tranfections of human HepG2 cells showed that the coNS3/4A gene gave 11-fold higher levels of NS3 as compared to the wtNS3/4A gene when using the CMV promoter. We have previously shown that the presence of NS4A enhances the expression by SFV. Both codon optimization and mRNA amplification resulted in an improved immunogenicity as evidenced by higher levels of NS3-specific antibodies. This improved immunogenicity also resulted in a more rapid priming of cytotoxic T lymphocytes (CTLs). Since HCV is a noncytolytic virus, the functionality of the primed CTL responses was evaluated by an in vivo challenge with NS3/4A-expressing syngeneic tumor cells. The priming of a tumor protective immunity required an endogenous production of the immunogen and CD8 þ CTLs, but was independent of B and CD4 þ T cells. This model confirmed the more rapid in vivo activation of an NS3/4A-specific tumor-inhibiting immunity by codon optimization and mRNA amplification. Finally, therapeutic vaccination with the coNS3/4A gene using gene gun 6-12 days after injection of tumors significantly reduced the tumor growth in vivo. Codon optimization and mRNA amplification effectively enhances the overall immunogenicity of NS3/4A. Thus, either, or both, of these approaches should be utilized in an NS3/4A-based HCV genetic vaccine.

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Cross-Priming as a Predominant Mechanism for Inducing CD8+ T Cell Responses in Gene Gun DNA Immunization

Cited by 96 publications

References 64 publications

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

DNA vaccination with T‐cell epitopes encoded within Ab molecules induces high‐avidity anti‐tumor CD8⁺ T cells

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

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Cross-Priming as a Predominant Mechanism for Inducing CD8+ T Cell Responses in Gene Gun DNA Immunization

Cited by 96 publications

References 64 publications

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

DNA vaccination with T‐cell epitopes encoded within Ab molecules induces high‐avidity anti‐tumor CD8+ T cells

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

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DNA vaccination with T‐cell epitopes encoded within Ab molecules induces high‐avidity anti‐tumor CD8⁺ T cells