The Capacity To Induce Cross-Presentation Dictates the Success of a TLR7 Agonist-Conjugate Vaccine for Eliciting Cellular Immunity

Oh, Jason Z.; Kedl, Ross M.

doi:10.4049/jimmunol.1001892

Cited by 58 publications

(57 citation statements)

References 29 publications

(45 reference statements)

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“…4C). These data are in line with our previous published results and those of others, showing that it is optimal to provide the antigen and the adjuvant in a conjugated form (8,12,14).…”

Section: Induction Of Antitumor Immunity By Tlr-l Peptide Conjugatessupporting

confidence: 83%

“…We have studied different clinically feasible TLR-L targeting systems to overcome the suboptimal CD8 þ CTL induction, to counteract improper polarization and regulation of T-cell responses, and to enhance peptide delivery to DCs. Several studies show that random coupling of TLR-L to protein antigen is an attractive approach to deliver antigens to DCs and induces an antigenspecific T-cell immune response (9)(10)(11)(12)(13). Likewise, coupling of minimal CTL epitopes to a synthetic TLR2-L has been reported to be an efficient vaccine modality (14).…”

Section: Activation and Induction Of T-cell Immunity Rely On Antigen mentioning

confidence: 99%

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Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Zom

Khan

Britten

et al. 2014

Cancer Immunology Research

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Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic synthetic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8þ T-cell immune responses. Previously, we have shown that the mechanism underlying the power of TLR-L SLP conjugates is improved delivery of the antigen together with a dendritic cell activation signal. In the present study, we have expanded the approach to tumor-specific CD4 þ as well as CD8 þ T-cell responses and in vivo studies in two nonrelated aggressive tumor models. We show that TLR2-L SLP conjugates have superior mouse CD8 þ and CD4

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“…4C). These data are in line with our previous published results and those of others, showing that it is optimal to provide the antigen and the adjuvant in a conjugated form (8,12,14).…”

Section: Induction Of Antitumor Immunity By Tlr-l Peptide Conjugatessupporting

confidence: 83%

Section: Activation and Induction Of T-cell Immunity Rely On Antigen mentioning

confidence: 99%

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Zom

Khan

Britten

et al. 2014

Cancer Immunology Research

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“…The modest increase in T-lymphocyte numbers in BALF might be related to the generation of CD8 1 responses and cross-priming induction, as described in imidazoquinoline conjugates. 34 Finally, although assessed in a prophylactic model, the increased IFN-g expression paralleled the in vitro results on human cells and the in vivo increase in allergen-specific IgG 2a antibody levels. Although the benefit of T H redirection versus immunoregulation in SIT is still a matter of debate, 24,25 SIT is aimed at modifying the pathogenic T H 2 arrangement, restoring a physiologic T H profile.…”

Section: Discussionmentioning

confidence: 60%

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Filì¹,

Vultaggio²,

Cardilicchia³

et al. 2013

Journal of Allergy and Clinical Immunology

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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T H -related transcription factors. Lung cells and sera of nDer p 2-Conjsensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-a production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T H 2-related cytokines and increased IFN-g levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-g upregulation together with IgE downregulation, and an increase in allergenspecific IgG 2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI 1 cells without inducing T H 17 cells or autoantibodies.

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“…Efficient cross-presentation is mediated by either prolonged residence of the Ag in the early endosome or decreased degradation in the late endosome (11)(12)(13). Dendritic cell (DC) cross-priming of the TLRmediated CTL response during microbial infection may not only upregulate costimulatory molecules but also regulate this process of cross-presentation (14)(15)(16)(17). However, the molecular mechanisms of TLR-mediated cross-presentation remain unclear.…”

mentioning

confidence: 99%

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Shen

Song

Chen

et al. 2014

The Journal of Immunology

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Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist–conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow–derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow–derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1–positive endosomes to RAS-related GTP-binding protein 7 (Rab7)–associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide–upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.

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The Capacity To Induce Cross-Presentation Dictates the Success of a TLR7 Agonist-Conjugate Vaccine for Eliciting Cellular Immunity

Cited by 58 publications

References 29 publications

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

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