The Role of Endoplasmic Reticulum-Associated Aminopeptidase 1 in Immunity to Infection and in Cross-Presentation

Firat, Elke; Saveanu, Loredana; Aichele, Peter; Staeheli, Peter; Huai, Jisen; Gaedicke, Simone; Nil, Ahmed; Besin, Gilles; Kanzler, Benoı̂t; Endert, Peter Van; Niedermann, Gabrielle

doi:10.4049/jimmunol.178.4.2241

Cited by 100 publications

(100 citation statements)

References 39 publications

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“…While further studies utilizing antigenpresentation assays in the presence or absence of biochemical inhibitors will enable deciphering these mechanisms, the use of MD as an OVA-delivery vehicle indeed reduces the threshold of OVA concentration required for effective cross-presentation by BMDC. This observation is consistent with previous studies, in which high concentrations of soluble OVA have been used to induce cross-presentation [31][32][33].…”

Section: Discussionsupporting

confidence: 93%

Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo

et al. 2008

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Antigen mannosylation has been shown to be an effective approach to potentiate antigen immunogenicity, due to the enhanced antigen uptake and presentation by APC. To overcome disadvantages associated with conventional methods used to mannosylate antigens, we have developed a novel mannose-based antigen delivery system that utilizes a polyamidoamine (PAMAM) dendrimer. It is demonstrated that mannosylated dendrimer ovalbumin (MDO) is a potent immune inducer. With a strong binding avidity to DC, MDO potently induced OVA-specific T cell response in vitro. It was found that the immunogenicity of MDO was due not only to enhanced antigen presentation, but also to induction of DC maturation. Mice immunized with MDO generated strong OVA-specific CD4 + /CD8 + T cell and antibody responses. MDO also targeted lymph node DC to crosspresent OVA, leading to OTI CD8 + T cell proliferation. Moreover, upon challenge with B16-OVA tumor cells, tumors in mice pre-immunized with MDO either did not grow or displayed a much more delayed onset, and had slower kinetics of growth than those of OVA-immunized mice. This mannose-based antigen delivery system was applied here for the first time to the immunization study. With several advantages and exceptional adjuvanticity, we propose mannosylated dendrimer as a potential vaccine carrier.

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Section: Discussionsupporting

confidence: 93%

Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo

et al. 2008

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“…The increase in GSW11 generation occurred despite an overall decrease in MHC I levels; MHC I downregulation is typically observed in ERAAP-knockout cells (Fig. 1D) (11)(12)(13)(14). This confirmed that the generation of GSW11 is ERAAP sensitive.…”

Section: Resultssupporting

confidence: 68%

“…In humans, two aminopeptidases perform this function, ERAP1 and ERAP2 (7)(8)(9); in mice, only one aminopeptidase exists, ERAAP (10). ERAAP is critical for the generation of many antigenic epitopes in vivo and can influence the generation of the antigenic peptide repertoire (11)(12)(13)(14). ERAAP can also destroy antigenic epitopes by trimming them to lengths too small for MHC binding, thus its characterization as an antigenic peptide editor (12).…”

mentioning

confidence: 99%

Induction of Protective Antitumor Immunity through Attenuation of ERAAP Function

James

Bailey

Sugiyarto

et al. 2013

The Journal of Immunology

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The endoplasmic reticulum aminopeptidase associated with Ag processing, ERAAP, plays an important role in the trimming of antigenic peptides for presentation at the cell surface complexed with MHC class I molecules. Tumors express varying levels of ERAAP, highlighting a possible mechanism of immune-evasion through alteration of the peptide repertoire. Using the CT26 tumor model, we investigated the effects of ERAAP modulation on peptide presentation and the use of ERAAP inhibition as an antitumor therapy. We show that generation of the cross-protective tumor Ag GSW11 in the colorectal carcinoma CT26 is increased when ERAAP expression is reduced. BALB/c mice with reduced ERAAP expression challenged with CT26 induced protective immunity that was mediated by CD8+ T cells. This antitumor immunity also protected mice when rechallenged with wild-type CT26 tumor; strong CD8+ T cell responses to GSW11 were observed, despite its presentation being considerably lower. Furthermore, boosting the tumor immunogenicity through inhibition of ERAAP function with the small molecule inhibitor leucinethiol in vitro, or in established tumors in vivo, abrogated tumor growth and prolonged survival. Thus, our results highlight the promising possibility of using modulation of ERAAP to generate protective antitumor responses as a strategy for cancer immunotherapy.

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“…As identifying antigenic peptides is difficult in the clinical setting, these double Tg mice (i.e., B27/ERAP Studies with ERAP-deficient mice have shown reduced cell surface expression of MHC I molecules, but not MHC II (10,11). These mice show no differences in the profile of CD4 and CD8 compared with mice with intact ERAP.…”

Section: /2mentioning

confidence: 99%

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

Akram

Lin

Gracey

et al. 2014

The Journal of Immunology

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Endoplasmic reticulum–associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383–391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383–391 epitope in influenza A (flu)–infected B27/ERAP−/− mice. With the use of tetramer staining, the number of naive CD8+ T cells expressing TCR Vβ8.1 in B27/ERAP−/− transgenic mice is significantly lower than that seen in B27/ERAP+/+ mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP−/− mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP+/+ mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP−/− transgenic mice. The B7-restricted NP418–426 CTL response in flu-infected B7/ERAP−/− and B7/ERAP+/+ mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition.

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The Role of Endoplasmic Reticulum-Associated Aminopeptidase 1 in Immunity to Infection and in Cross-Presentation

Cited by 100 publications

References 39 publications

Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo

Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo

Induction of Protective Antitumor Immunity through Attenuation of ERAAP Function

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

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