In Vivo, Dendritic Cells Can Cross-Present Virus-Like Particles Using an Endosome-to-Cytosol Pathway

Morón, Víctor Gabriel; Rueda, Paloma; Sedlik, Christine

doi:10.4049/jimmunol.171.5.2242

Cited by 102 publications

(82 citation statements)

References 78 publications

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“…As for many other exogenous Ags, cross-presentation of OVA by DCs involves degradation of OVA fragments by the proteasome (56,57). To determine whether the proteasome is still required for OVA degradation upon polyU stimulation in DCs, we repeated the CD8 + T cell proliferation assay preincubating DCs with polyU/ DO plus OVA and lactacystin, a specific proteasome inhibitor (58,59).…”

Section: Priming Of Cd8 + T Cells By Polyu Requires Ag Translocation mentioning

confidence: 99%

TLR7 Triggering with Polyuridylic Acid Promotes Cross-Presentation in CD8α+ Conventional Dendritic Cells by Enhancing Antigen Preservation and MHC Class I Antigen Permanence on the Dendritic Cell Surface

Crespo

Zacca

Núñez

et al. 2013

The Journal of Immunology

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ssRNA can interact with dendritic cells (DCs) through binding to TLR7, inducing secretion of proinflammatory cytokines and type I IFN. Triggering TLR7 enhances cross-priming of CD8+ T cells, which requires cross-presentation of exogenous Ag to DCs. However, how TLR triggering can affect Ag cross-presentation is still not clear. Using OVA as an Ag model, we observed that stimulation of TLR7 in DCs by polyuridylic acid (polyU), a synthetic ssRNA analog, generates a strong specific cytotoxic response in C57BL/6 mice. PolyU stimulate CD8α+ DCs to cross-prime naive CD8+ T cells in a type I IFN–dependent fashion. This enhanced cross-priming is accompanied by a higher density of OVA256-264/H-2Kb complexes on CD8α+ DCs treated with polyU, as well as by upregulation of costimulatory molecules and increased secretion of proinflammatory cytokines by DCs. Cross-priming of CD8+ T cells by DCs treated with polyU requires proteasome and Ag translocation to cytosol through the Sec61 channel in DCs. The observed enhancement in OVA cross-presentation with polyU in DCs could be mediated by a limited Ag degradation in endophagosomal compartments and a higher permanence of OVA peptide/MHC class I complexes on DCs. These observations clearly reveal that key steps of Ag processing for cross-presentation can be modulated by TLR ligands, opening new avenues for understanding their mechanisms as adjuvants of the immune response.

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Section: Priming Of Cd8 + T Cells By Polyu Requires Ag Translocation mentioning

confidence: 99%

TLR7 Triggering with Polyuridylic Acid Promotes Cross-Presentation in CD8α+ Conventional Dendritic Cells by Enhancing Antigen Preservation and MHC Class I Antigen Permanence on the Dendritic Cell Surface

Crespo

Zacca

Núñez

et al. 2013

The Journal of Immunology

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“…In these cells, macropinosomes are important for major histocompatibility complex class I and class II presentation of exogenous antigens, including viruses and Fc␥ receptor (Fc␥-R)-bound ligands (1,22,27,39,46). In addition, they are involved in phagocytosing large particles during innate and adaptive immune responses through various cell surface receptors, including Fc-Rs.…”

mentioning

confidence: 99%

Early Steps of Clathrin-Mediated Endocytosis Involved in Phagosomal Escape of Fcγ Receptor-Targeted Adenovirus

Meier¹,

Gastaldelli²,

Boucke³

et al. 2005

J Virol

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“…Replicating vectors, although attenuated, also come with a risk of toxicity. A promising approach is to use recombinant virus-like particles that are nonreplicating but mimic viral Ag delivery pathways (41). We have previously demonstrated the ability of archaeosomes to activate DC costimulation and augment CTL responses to entrapped Ag.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylserine Receptor-Mediated Recognition of Archaeosome Adjuvant Promotes Endocytosis and MHC Class I Cross-Presentation of the Entrapped Antigen by Phagosome-to-Cytosol Transport and Classical Processing

Gurnani

Kennedy

Sad

et al. 2004

The Journal of Immunology

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Archaeal isopranoid glycerolipid vesicles (archaeosomes) serve as strong adjuvants for cell-mediated responses to entrapped Ag. We analyzed the processing pathway of OVA entrapped in archaeosomes composed of Methanobrevibacter smithii lipids, high in archaetidylserine (OVA-archaeosomes). In vitro, OVA-archaeosomes stimulated spleen cells from OVA-TCR-transgenic mice, D011.10 (CD4+ cells expressing OVA323–339 TCR) or OT1 (>90% CD8+ OVA257–264 cells), indicating both MHC class I and II presentations. In vivo, when naive (Thy1.2+) CFSE-labeled OT1 cells were transferred into OVA-archaeosome-immunized Thy 1.1+ recipient mice, there was profound accumulation and cycling of donor-specific cells, and differentiation of H-2KbOva257–264 CD8+ T cells into CD44highCD62Llow effectors. Both macrophages and dendritic cells (DCs) efficiently cross-presented OVA-archaeosomes on MHC class I. Blocking phagocytosis by phosphatidylserine-specific receptor agonists strongly inhibited MHC class I presentation of OVA-archaeosomes, whereas blocking mannose receptors or FcRs lacked effect, indicating specific recognition of the archaetidylserine head group of M. smithii lipids by APCs. In addition, inhibitors of endosomal acidification blocked MHC class I processing of OVA-archaeosomes, whereas endosomal protease inhibitors lacked effect, suggesting acidification-dependent phagosome-to-cytosol diversion. Proteasomal inhibitors blocked OVA-archaeosome MHC class I presentation, confirming cytosolic processing. Both in vitro and in vivo, OVA-archaeosome MHC class I presentation required TAP. Ag-free archaeosomes also activated DC costimulation and cytokine production, without overt inflammation. Phosphatidylserine-specific receptor-mediated endocytosis is a mechanism of apoptotic cell clearance and DCs cross-present Ags sampled from apoptotic cells. Our results reveal the novel ability of archaeosomes to exploit this mechanism for cytosolic MHC class I Ag processing, and provide an effective particulate vaccination strategy.

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In Vivo, Dendritic Cells Can Cross-Present Virus-Like Particles Using an Endosome-to-Cytosol Pathway

Cited by 102 publications

References 78 publications

TLR7 Triggering with Polyuridylic Acid Promotes Cross-Presentation in CD8α+ Conventional Dendritic Cells by Enhancing Antigen Preservation and MHC Class I Antigen Permanence on the Dendritic Cell Surface

TLR7 Triggering with Polyuridylic Acid Promotes Cross-Presentation in CD8α+ Conventional Dendritic Cells by Enhancing Antigen Preservation and MHC Class I Antigen Permanence on the Dendritic Cell Surface

Early Steps of Clathrin-Mediated Endocytosis Involved in Phagosomal Escape of Fcγ Receptor-Targeted Adenovirus

Phosphatidylserine Receptor-Mediated Recognition of Archaeosome Adjuvant Promotes Endocytosis and MHC Class I Cross-Presentation of the Entrapped Antigen by Phagosome-to-Cytosol Transport and Classical Processing

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