Limits...
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 DEC-205. Adjuvant-free immunization of mice with antigen-conjugated anti-DEC-205 antibodies leads to regulatory T-cell-dependent tolerance. In contrast, co-injection of an adjuvant with anti-DEC-205 primes a robust cytotoxic T-cell immune response. It also strongly activates a CD4+ T-cell immune response leading to generation of Th cells that support the humoral response.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4815026&req=5

fig1: Immune responses elicited by antigen targeting to DEC-205. Adjuvant-free immunization of mice with antigen-conjugated anti-DEC-205 antibodies leads to regulatory T-cell-dependent tolerance. In contrast, co-injection of an adjuvant with anti-DEC-205 primes a robust cytotoxic T-cell immune response. It also strongly activates a CD4+ T-cell immune response leading to generation of Th cells that support the humoral response.

Mentions: Pioneering work has demonstrated the principle of DC targeting using antigen-conjugated antibodies specific to the C-type lectin receptor DEC-205 (Figure 1). In mice, DEC-205 expression is predominant on thymic epithelial cells and DCs, including CD8+ DCs, dermal DCs and LCs.57 In humans, DEC-205 is expressed at high levels on mDCs and monocytes, at intermediate levels by B cells and at low levels on natural killer cells, T cells and pDCs.58 A major function of this endocytic receptor is suggested to involve binding dying cells for uptake and cross-presentation of debris-associated antigens by DCs.59 DEC-205 also binds to the class B CpG oligonucleotide, a synthetic TLR-9 ligand, and enables its uptake.60 Several reports have demonstrated that ex vivo targeting of mouse DCs, and more specifically CD8+ DCs, with ovalbumin (OVA)-conjugated anti-DEC-205 antibodies induces robust MHC-I cross-presentation to OVA-specific CD8+ T cells. Furthermore, these conjugates elicit high OVA presentation by MHC-II molecules, and this process is enhanced following targeting of CD8− DCs, despite their low expression of DEC205, relative to CD8+ DCs.55, 61, 62, 63In vivo, injection of OVA-conjugated rat anti-DEC205 antibodies into mice, in the presence of an adjuvant, also induces substantial proliferation and accumulation of OVA-specific naive CD8+ and CD4+ T cells, leading to their differentiation into effector T cells.55, 61, 62, 63, 64 Interestingly, this process is concomitant with prolonged antigen presentation by MHC-I, but not by MHC-II molecules.63 Injected mice also display a strong humoral response with high levels of anti-rat and anti-OVA antibodies detected in the serum.64 Using irradiated mice reconstituted with equal ratios of DEC-205+/+ and DEC-205−/− bone marrow, we have shown that only targeted DCs, but not non-targeted DCs, are responsible for MHC-I and MHC-II presentation in response to DEC205 targeting in vivo.65 Importantly, the administration of an adjuvant, along with antigen-conjugated anti-DEC-205 antibodies, is a prerequisite to induce a robust T-cell immune response.55, 61, 62, 63, 64 In the absence of a DC maturation signal, the delivery of antigens to DEC-205 in vivo is associated with T-cell tolerance. In this case, an initial expansion of antigen-specific CD8+ and CD4+ T cells occurs, but these cells do not differentiate into effector T cells and are ultimately deleted.55, 66 Furthermore, mice that are immunized in these settings become unresponsive to rechallenge with the same unconjugated antigen.62 Interestingly, Mahnke et al.67 have reported that DEC-205 targeting under these conditions leads to the activation of CD25+ regulatory T cells, again suggesting the induction of peripheral T-cell tolerance. For B-cell-mediated immunity induced by DEC205 targeting, the requirement for an adjuvant remains unclear. Indeed, although in some studies a potent anti-rat humoral response is observed following adjuvant-free immunization with rat anti-DEC205 antibodies,68 others report very poor antibody responses in mice immunized in a similar manner.64 This may be due to the specific antibody used for targeting given that in the absence of adjuvant, significant differences in the IgG response to different anti-DEC205 antibodies are observed.68 This suggests that targeting outcomes will be impacted by inherent properties of the targeting antibodies themselves.


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 DEC-205. Adjuvant-free immunization of mice with antigen-conjugated anti-DEC-205 antibodies leads to regulatory T-cell-dependent tolerance. In contrast, co-injection of an adjuvant with anti-DEC-205 primes a robust cytotoxic T-cell immune response. It also strongly activates a CD4+ T-cell immune response leading to generation of Th cells that support the humoral response.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Immune responses elicited by antigen targeting to DEC-205. Adjuvant-free immunization of mice with antigen-conjugated anti-DEC-205 antibodies leads to regulatory T-cell-dependent tolerance. In contrast, co-injection of an adjuvant with anti-DEC-205 primes a robust cytotoxic T-cell immune response. It also strongly activates a CD4+ T-cell immune response leading to generation of Th cells that support the humoral response.
Mentions: Pioneering work has demonstrated the principle of DC targeting using antigen-conjugated antibodies specific to the C-type lectin receptor DEC-205 (Figure 1). In mice, DEC-205 expression is predominant on thymic epithelial cells and DCs, including CD8+ DCs, dermal DCs and LCs.57 In humans, DEC-205 is expressed at high levels on mDCs and monocytes, at intermediate levels by B cells and at low levels on natural killer cells, T cells and pDCs.58 A major function of this endocytic receptor is suggested to involve binding dying cells for uptake and cross-presentation of debris-associated antigens by DCs.59 DEC-205 also binds to the class B CpG oligonucleotide, a synthetic TLR-9 ligand, and enables its uptake.60 Several reports have demonstrated that ex vivo targeting of mouse DCs, and more specifically CD8+ DCs, with ovalbumin (OVA)-conjugated anti-DEC-205 antibodies induces robust MHC-I cross-presentation to OVA-specific CD8+ T cells. Furthermore, these conjugates elicit high OVA presentation by MHC-II molecules, and this process is enhanced following targeting of CD8− DCs, despite their low expression of DEC205, relative to CD8+ DCs.55, 61, 62, 63In vivo, injection of OVA-conjugated rat anti-DEC205 antibodies into mice, in the presence of an adjuvant, also induces substantial proliferation and accumulation of OVA-specific naive CD8+ and CD4+ T cells, leading to their differentiation into effector T cells.55, 61, 62, 63, 64 Interestingly, this process is concomitant with prolonged antigen presentation by MHC-I, but not by MHC-II molecules.63 Injected mice also display a strong humoral response with high levels of anti-rat and anti-OVA antibodies detected in the serum.64 Using irradiated mice reconstituted with equal ratios of DEC-205+/+ and DEC-205−/− bone marrow, we have shown that only targeted DCs, but not non-targeted DCs, are responsible for MHC-I and MHC-II presentation in response to DEC205 targeting in vivo.65 Importantly, the administration of an adjuvant, along with antigen-conjugated anti-DEC-205 antibodies, is a prerequisite to induce a robust T-cell immune response.55, 61, 62, 63, 64 In the absence of a DC maturation signal, the delivery of antigens to DEC-205 in vivo is associated with T-cell tolerance. In this case, an initial expansion of antigen-specific CD8+ and CD4+ T cells occurs, but these cells do not differentiate into effector T cells and are ultimately deleted.55, 66 Furthermore, mice that are immunized in these settings become unresponsive to rechallenge with the same unconjugated antigen.62 Interestingly, Mahnke et al.67 have reported that DEC-205 targeting under these conditions leads to the activation of CD25+ regulatory T cells, again suggesting the induction of peripheral T-cell tolerance. For B-cell-mediated immunity induced by DEC205 targeting, the requirement for an adjuvant remains unclear. Indeed, although in some studies a potent anti-rat humoral response is observed following adjuvant-free immunization with rat anti-DEC205 antibodies,68 others report very poor antibody responses in mice immunized in a similar manner.64 This may be due to the specific antibody used for targeting given that in the absence of adjuvant, significant differences in the IgG response to different anti-DEC205 antibodies are observed.68 This suggests that targeting outcomes will be impacted by inherent properties of the targeting antibodies themselves.

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.