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Targeting dendritic cells: a promising strategy to improve vaccine effectiveness.

Macri C, Dumont C, Johnston AP, Mintern JD - Clin Transl Immunology (2016)

Bottom Line: This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs.Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting.We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University , Clayton, Victoria, Australia.

ABSTRACT
Dendritic cell (DC) targeting is a novel strategy to enhance vaccination efficacy. This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs. Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting. We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses. Finally, we discuss the intracellular trafficking criteria of the targeted receptors that may impact their effectiveness as DC targets.

No MeSH data available.


Immune responses elicited by antigen targeting to Clec9A. At steady state, some antigen-conjugated anti-Clec9A antibodies generate regulatory T cells that lead to tolerance. Alternatively, other anti-Clec9A antibodies activate a robust humoral response that involves the production of Tfh. Antigen delivery to DCs via Clec9A also elicits a strong CTL immune response that requires adjuvant administration.
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fig2: Immune responses elicited by antigen targeting to Clec9A. At steady state, some antigen-conjugated anti-Clec9A antibodies generate regulatory T cells that lead to tolerance. Alternatively, other anti-Clec9A antibodies activate a robust humoral response that involves the production of Tfh. Antigen delivery to DCs via Clec9A also elicits a strong CTL immune response that requires adjuvant administration.

Mentions: Clec9A (also known as DNGR-1) is a C-type lectin-like receptor. In mice, its expression is restricted to DCs with high levels measured on CD8+ DCs and lower levels on pDCs.11, 12 In humans, Clec9A is highly expressed by CD141+ DCs, the human equivalents of the CD8+ DCs, however, not by pDC.11, 12 Clec9A is a critical receptor for cross-presentation of dead cell-associated antigen by DC.76, 77 This process relies on recognition of an actin-containing cytoskeletal structure that is exposed on apoptotic and necrotic cells when the cell membrane is ruptured.77, 78 Interestingly, several studies have exploited the natural function of Clec9A in antigen presentation, using it as a target receptor for vaccine enhancement (Figure 2). In vivo injection of anti-Clec9A antibodies specifically labels CD8+ DCs and pDCs.11, 79, 80 To determine whether Clec9A was a promising receptor for DC targeting, OVA was genetically conjugated to anti-Clec9A antibodies and the resulting conjugates administrated to mice. At steady state, these conjugates induce the proliferation of OVA-specific transgenic CD8+ and CD4+ T cells, showing that antigen targeted to Clec9A is efficiently processed and presented by MHC-I and MHC-II molecules.12 Furthermore, Sancho et al.11 have shown that delivering OVA to DCs via Clec9A in vivo, together with an adjuvant, leads to a cytotoxic T lymphocyte response that actively suppresses OVA-expressing lung metastases. Similar results are observed when the vaccine is administered prior or after tumor challenge, showing that targeting antigen to Clec9A can be used as a vaccine for prophylaxis or immunotherapy.11 In another report, Joffre et al. highlight that in vivo injection of anti-Clec9A antibodies conjugated to an MHC-II-binding OVA peptide, together with an adjuvant, leads to robust CD4+ T-cell priming. In this case, the nature of the adjuvant used dictates the polarization of effector CD4+ T cells. For instance, poly I:C induces the differentiation of activated CD4+ T cells into Th1, leading to a strong humoral response. In contrast, curdlan co-injection primes a Th17 immune response.79 Adjuvant-free immunization with anti-Clec9A antibodies is reported to give rise to Foxp3+ T cells and to reduce antibody production, suggesting the induction of tolerance.79 However, in direct contrast to these data, other authors report that antigen delivery via Clec9A enhances the humoral response even in the absence of adjuvant. Mice injected with rat anti-Clec9A antibodies conjugated to OVA produce high-serum titers of anti-rat IgG and anti-OVA antibodies at steady state.12, 64 Furthermore, the use of Myd88−/− TRIF−/− mice, deficient in TLR signaling, does not impair this humoral response, ruling out possible endotoxin contamination of the anti-Clec9A antibodies acting to compensate for the absence of adjuvant.12 Park et al. have also measured the humoral response upon adjuvant-free injection of rat anti-Clec9A antibodies conjugated to hapten nitrophenol (NP). In line with the previous data, high and prolonged levels of anti-rat IgG and anti-NP antibodies are detected in the serum, encompassing all IgG isotypes.81 A strong anti-rat IgG humoral response was also induced in non-human primates immunized with rat anti-Clec9A antibodies only.82 The discrepancy between studies regarding the requirement of an adjuvant for the antibody response following Clec9A targeting may originate in the type of injected antibody. Joffre et al.79 injected a rat IgG1 anti-Clec9A antibody, whereas others have used a rat IgG2a isotype12, 64, 81, 82 that is inherently more immunogenic.82 In contrast, the adjuvant-free immunogenicity of the anti-Clec9A antibodies cannot be predicted from the targeted region of the receptor, the binding capacities to the target in vivo or the persistence of the targeting antibodies in the serum.82


Targeting dendritic cells: a promising strategy to improve vaccine effectiveness.

Macri C, Dumont C, Johnston AP, Mintern JD - Clin Transl Immunology (2016)

Immune responses elicited by antigen targeting to Clec9A. At steady state, some antigen-conjugated anti-Clec9A antibodies generate regulatory T cells that lead to tolerance. Alternatively, other anti-Clec9A antibodies activate a robust humoral response that involves the production of Tfh. Antigen delivery to DCs via Clec9A also elicits a strong CTL immune response that requires adjuvant administration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4815026&req=5

fig2: Immune responses elicited by antigen targeting to Clec9A. At steady state, some antigen-conjugated anti-Clec9A antibodies generate regulatory T cells that lead to tolerance. Alternatively, other anti-Clec9A antibodies activate a robust humoral response that involves the production of Tfh. Antigen delivery to DCs via Clec9A also elicits a strong CTL immune response that requires adjuvant administration.
Mentions: Clec9A (also known as DNGR-1) is a C-type lectin-like receptor. In mice, its expression is restricted to DCs with high levels measured on CD8+ DCs and lower levels on pDCs.11, 12 In humans, Clec9A is highly expressed by CD141+ DCs, the human equivalents of the CD8+ DCs, however, not by pDC.11, 12 Clec9A is a critical receptor for cross-presentation of dead cell-associated antigen by DC.76, 77 This process relies on recognition of an actin-containing cytoskeletal structure that is exposed on apoptotic and necrotic cells when the cell membrane is ruptured.77, 78 Interestingly, several studies have exploited the natural function of Clec9A in antigen presentation, using it as a target receptor for vaccine enhancement (Figure 2). In vivo injection of anti-Clec9A antibodies specifically labels CD8+ DCs and pDCs.11, 79, 80 To determine whether Clec9A was a promising receptor for DC targeting, OVA was genetically conjugated to anti-Clec9A antibodies and the resulting conjugates administrated to mice. At steady state, these conjugates induce the proliferation of OVA-specific transgenic CD8+ and CD4+ T cells, showing that antigen targeted to Clec9A is efficiently processed and presented by MHC-I and MHC-II molecules.12 Furthermore, Sancho et al.11 have shown that delivering OVA to DCs via Clec9A in vivo, together with an adjuvant, leads to a cytotoxic T lymphocyte response that actively suppresses OVA-expressing lung metastases. Similar results are observed when the vaccine is administered prior or after tumor challenge, showing that targeting antigen to Clec9A can be used as a vaccine for prophylaxis or immunotherapy.11 In another report, Joffre et al. highlight that in vivo injection of anti-Clec9A antibodies conjugated to an MHC-II-binding OVA peptide, together with an adjuvant, leads to robust CD4+ T-cell priming. In this case, the nature of the adjuvant used dictates the polarization of effector CD4+ T cells. For instance, poly I:C induces the differentiation of activated CD4+ T cells into Th1, leading to a strong humoral response. In contrast, curdlan co-injection primes a Th17 immune response.79 Adjuvant-free immunization with anti-Clec9A antibodies is reported to give rise to Foxp3+ T cells and to reduce antibody production, suggesting the induction of tolerance.79 However, in direct contrast to these data, other authors report that antigen delivery via Clec9A enhances the humoral response even in the absence of adjuvant. Mice injected with rat anti-Clec9A antibodies conjugated to OVA produce high-serum titers of anti-rat IgG and anti-OVA antibodies at steady state.12, 64 Furthermore, the use of Myd88−/− TRIF−/− mice, deficient in TLR signaling, does not impair this humoral response, ruling out possible endotoxin contamination of the anti-Clec9A antibodies acting to compensate for the absence of adjuvant.12 Park et al. have also measured the humoral response upon adjuvant-free injection of rat anti-Clec9A antibodies conjugated to hapten nitrophenol (NP). In line with the previous data, high and prolonged levels of anti-rat IgG and anti-NP antibodies are detected in the serum, encompassing all IgG isotypes.81 A strong anti-rat IgG humoral response was also induced in non-human primates immunized with rat anti-Clec9A antibodies only.82 The discrepancy between studies regarding the requirement of an adjuvant for the antibody response following Clec9A targeting may originate in the type of injected antibody. Joffre et al.79 injected a rat IgG1 anti-Clec9A antibody, whereas others have used a rat IgG2a isotype12, 64, 81, 82 that is inherently more immunogenic.82 In contrast, the adjuvant-free immunogenicity of the anti-Clec9A antibodies cannot be predicted from the targeted region of the receptor, the binding capacities to the target in vivo or the persistence of the targeting antibodies in the serum.82

Bottom Line: This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs.Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting.We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University , Clayton, Victoria, Australia.

ABSTRACT
Dendritic cell (DC) targeting is a novel strategy to enhance vaccination efficacy. This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs. Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting. We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses. Finally, we discuss the intracellular trafficking criteria of the targeted receptors that may impact their effectiveness as DC targets.

No MeSH data available.