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Article ; Online: Involvement of autophagy in MHC class I antigen presentation.

Øynebråten, Inger

2020 Volume 92, Issue 5, Page(s) e12978

Abstract: MHC class I molecules on the cellular surface display peptides that either derive from endogenous proteins (self or viral), or from endocytosis of molecules, dying cells or pathogens. The conventional antigen-processing pathway for MHC class I ... ...

Abstract	MHC class I molecules on the cellular surface display peptides that either derive from endogenous proteins (self or viral), or from endocytosis of molecules, dying cells or pathogens. The conventional antigen-processing pathway for MHC class I presentation depends on proteasome-mediated degradation of the protein followed by transporter associated with antigen-processing (TAP)-mediated transport of the generated peptides into the endoplasmic reticulum (ER). Here, peptides are loaded onto MHC I molecules before transportation to the cell surface. However, several alternative mechanisms have emerged. These include TAP-independent mechanisms, the vacuolar pathway and involvement of autophagy. Autophagy is a cell intrinsic recycling system. It also functions as a defence mechanism that removes pathogens and damaged endocytic compartments from the cytosol. Therefore, it appears likely that autophagy would intersect with the MHC class I presentation pathway to alarm CD8
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Antigens/immunology ; Antigens/metabolism ; Autophagy/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Endoplasmic Reticulum/immunology ; Endoplasmic Reticulum/metabolism ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Proteasome Endopeptidase Complex/immunology ; Proteasome Endopeptidase Complex/metabolism ; Protein Transport/immunology
Chemical Substances	Antigens ; Histocompatibility Antigens Class I ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2020-10-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	120476-2
ISSN	1365-3083 ; 0300-9475
ISSN (online)	1365-3083
ISSN	0300-9475
DOI	10.1111/sji.12978
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Article ; Online: Fungal polysaccharides from Inonotus obliquus are agonists for Toll-like receptors and induce macrophage anti-cancer activity.

Wold, Christian Winther / Christopoulos, Panagiotis F / Arias, Maykel A / Dzovor, Deborah Elikplim / Øynebråten, Inger / Corthay, Alexandre / Inngjerdingen, Kari Tvete

Communications biology

2024 Volume 7, Issue 1, Page(s) 222

Abstract: Fungal polysaccharides can exert immunomodulating activity by triggering pattern recognition receptors (PRRs) on innate immune cells such as macrophages. Here, we evaluate six polysaccharides isolated from the medicinal fungus Inonotus obliquus for their ...

Abstract	Fungal polysaccharides can exert immunomodulating activity by triggering pattern recognition receptors (PRRs) on innate immune cells such as macrophages. Here, we evaluate six polysaccharides isolated from the medicinal fungus Inonotus obliquus for their ability to activate mouse and human macrophages. We identify two water-soluble polysaccharides, AcF1 and AcF3, being able to trigger several critical antitumor functions of macrophages. AcF1 and AcF3 activate macrophages to secrete nitric oxide and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Combined with interferon-γ, the fungal polysaccharides trigger high production of IL-12p70, a central cytokine for antitumor immunity, and induce macrophage-mediated inhibition of cancer cell growth in vitro and in vivo. AcF1 and AcF3 are strong agonists of the PRRs Toll-like receptor 2 (TLR2) and TLR4, and weak agonists of Dectin-1. In comparison, two prototypical particulate β-glucans, one isolated from I. obliquus and one from Saccharomyces cerevisiae (zymosan), are agonists for Dectin-1 but not TLR2 or TLR4, and are unable to trigger anti-cancer functions of macrophages. We conclude that the water-soluble polysaccharides AcF1 and AcF3 from I. obliquus have a strong potential for cancer immunotherapy by triggering multiple PRRs and by inducing potent anti-cancer activity of macrophages.
MeSH term(s)	Mice ; Humans ; Animals ; Fungal Polysaccharides/pharmacology ; Toll-Like Receptor 4 ; Lectins, C-Type ; Toll-Like Receptors ; Macrophages ; Cytokines ; Water ; Inonotus
Chemical Substances	Fungal Polysaccharides ; Toll-Like Receptor 4 ; Lectins, C-Type ; Toll-Like Receptors ; Cytokines ; Water (059QF0KO0R)
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05853-y
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Article: Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells.

Eek Mariampillai, Adrian / Hauge, Sissel / Øynebråten, Inger / Rødland, Gro Elise / Corthay, Alexandre / Syljuåsen, Randi G

Frontiers in oncology

2022 Volume 12, Page(s) 981332

Abstract: Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR ... ...

Abstract	Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 checkpoint, increase cGAS-mediated type I IFN response after irradiation in human lung cancer and osteosarcoma cell lines. Supporting that the checkpoint may prevent IFN induction, radiation-induced IFN signaling declined when the G2 checkpoint arrest was prolonged at high radiation doses. G2 checkpoint abrogation after co-treatment with radiation and ATR inhibitors was accompanied by increased radiation-induced IFN signaling in four out of five cell lines tested. Consistent with the hypothesis that the cytosolic DNA sensor cGAS may detect DNA from ruptured micronuclei after G2 checkpoint abrogation, cGAS co-localized with micronuclei, and depletion of cGAS or STING abolished the IFN responses. Contrastingly, one lung cancer cell line showed no increase in IFN signaling despite irradiation and G2 checkpoint abrogation. This cell line showed a higher level of the exonuclease TREX1 than the other cell lines, but TREX1 depletion did not enhance IFN signaling. Rather, addition of a pan-caspase inhibitor restored the IFN response in this cell line and also increased the responses in the other cell lines. These results show that treatment-induced caspase activation can suppress the IFN response after co-treatment with radiation and ATR inhibitors. Caspase activation thus warrants further consideration as a possible predictive marker for lack of IFN signaling.
Language	English
Publishing date	2022-10-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.981332
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Article ; Online: On antigen-specific signals, immune class regulation and energetics: Report III from the workshops on foundational concepts of immune regulation.

Anderson, Colin C / Bonney, Elizabeth A / Mueller, Thomas F / Corthay, Alexandre / Havele, Calliopi / Singh, Nevil J / Øynebråten, Inger / Bretscher, Peter A

Scandinavian journal of immunology

2023 Volume 98, Issue 3, Page(s) e13311

Abstract: This is a report from a one-week workshop held in Athens, Greece in July of 2022. The workshop aimed to identify emerging concepts relevant to the fundamentals of immune regulation and areas for future research. Theories of immune regulation emphasize ... ...

Abstract	This is a report from a one-week workshop held in Athens, Greece in July of 2022. The workshop aimed to identify emerging concepts relevant to the fundamentals of immune regulation and areas for future research. Theories of immune regulation emphasize the role of T cell help or co-stimulation (signal 2). The workshop participants considered how new data on the characteristics of agonist antigens, the role of the antigen receptor signals (signal 1) in driving fate decisions, the effect of energetics on immunity and a better understanding of class-control in the immune response, may impact theories of immune regulation. These ideas were discussed in the context of tumour immunology, autoimmunity, pregnancy and transplantation. Here we present the discussions as a narrative of different viewpoints to allow the reader to join the conversation. These discussions highlight the evolving understanding of the nature of specific antigen recognition and how both antigen-specific and non-specific mechanisms impact immune responses.
MeSH term(s)	Humans ; Antigens ; T-Lymphocytes ; Autoimmunity
Chemical Substances	Antigens
Language	English
Publishing date	2023-07-11
Publishing country	England
Document type	Journal Article
ZDB-ID	120476-2
ISSN	1365-3083 ; 0300-9475
ISSN (online)	1365-3083
ISSN	0300-9475
DOI	10.1111/sji.13311
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Article ; Online: The Immune Landscape of Human Primary Lung Tumors Is Th2 Skewed.

Frafjord, Astri / Buer, Linn / Hammarström, Clara / Aamodt, Henrik / Woldbæk, Per Reidar / Brustugun, Odd Terje / Helland, Åslaug / Øynebråten, Inger / Corthay, Alexandre

Frontiers in immunology

2021 Volume 12, Page(s) 764596

Abstract: Tumor-specific T helper (Th) cells have a central role in the immune response against cancer. However, there exist distinct Th cell subsets with very different and antagonizing properties. Some Th subsets such as Th1 protect against cancer, while others ( ...

Abstract	Tumor-specific T helper (Th) cells have a central role in the immune response against cancer. However, there exist distinct Th cell subsets with very different and antagonizing properties. Some Th subsets such as Th1 protect against cancer, while others (Th2, T regulatory/Treg) are considered detrimental or of unknown significance (T follicular helper/Tfh, Th17). The Th composition of human solid tumors remains poorly characterized. Therefore, we established a four-color multiplex chromogenic immunohistochemical assay for detection of Th1, Th2, Th17, Tfh and Treg cells in human tumor sections. The method was used to analyze resected primary lung tumors from 11 patients with non-small cell lung cancer (NSCLC). Four microanatomical regions were investigated: tumor epithelium, tumor stroma, peritumoral tertiary lymphoid structures (TLS) and non-cancerous distal lung tissue. In tumor epithelium and stroma, most CD4
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Lung Neoplasms/immunology ; Male ; Middle Aged ; Th2 Cells/immunology
Language	English
Publishing date	2021-11-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.764596
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Article ; Online: The immune microenvironment in typical carcinoid lung tumour, a brief report of four cases.

Stankovic, Branislava / Aamodt, Henrik / Bjørhovde, Heidi Anine Korsmo / Müller, Elisabeth / Hammarström, Clara / Brustugun, Odd Terje / Helland, Åslaug / Øynebråten, Inger / Corthay, Alexandre

Scandinavian journal of immunology

2020 Volume 92, Issue 2, Page(s) e12893

Abstract: Pulmonary typical carcinoid (TC) is a low-grade, rare lung cancer of neuroendocrine origin. Currently, there is very little information available about the immune cell composition in TC tumours. Here, we analysed by flow cytometry resected tumours from ... ...

Abstract	Pulmonary typical carcinoid (TC) is a low-grade, rare lung cancer of neuroendocrine origin. Currently, there is very little information available about the immune cell composition in TC tumours. Here, we analysed by flow cytometry resected tumours from four never-smoker female patients with TC. Twelve distinct immune cell types were identified in TC tumours. The most abundant immune cells were CD8
MeSH term(s)	Adult ; Aged ; Carcinoid Tumor/immunology ; Female ; Humans ; Lung Neoplasms/immunology ; Middle Aged ; Tumor Microenvironment/immunology
Language	English
Publishing date	2020-06-09
Publishing country	England
Document type	Journal Article
ZDB-ID	120476-2
ISSN	1365-3083 ; 0300-9475
ISSN (online)	1365-3083
ISSN	0300-9475
DOI	10.1111/sji.12893
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Article ; Online: Lactobacillus plantarum displaying CCL3 chemokine in fusion with HIV-1 Gag derived antigen causes increased recruitment of T cells.

Kuczkowska, Katarzyna / Mathiesen, Geir / Eijsink, Vincent G H / Øynebråten, Inger

Microbial cell factories

2015 Volume 14, Page(s) 169

Abstract: Background: Chemokines are attractive candidates for vaccine adjuvants due to their ability to recruit the immune cells. Lactic acid bacteria (LAB)-based delivery vehicles have potential to be used as a cheap and safe option for vaccination. Chemokine ... ...

Abstract	Background: Chemokines are attractive candidates for vaccine adjuvants due to their ability to recruit the immune cells. Lactic acid bacteria (LAB)-based delivery vehicles have potential to be used as a cheap and safe option for vaccination. Chemokine produced on the surface of LAB may potentially enhance the immune response to an antigen and this approach can be considered in development of future mucosal vaccines. Results: We have constructed strains of Lactobacillus plantarum displaying a chemokine on their surface. L. plantarum was genetically engineered to express and anchor to the surface a protein called CCL3Gag. CCL3Gag is a fusion protein comprising of truncated HIV-1 Gag antigen and the murine chemokine CCL3, also known as MIP-1α. Various surface anchoring strategies were explored: (1) a lipobox-based covalent membrane anchor, (2) sortase-mediated covalent cell wall anchoring, (3) LysM-based non-covalent cell wall anchoring, and (4) an N-terminal signal peptide-based transmembrane anchor. Protein production and correct localization were confirmed using Western blotting, flow cytometry and immunofluorescence microscopy. Using a chemotaxis assay, we demonstrated that CCL3Gag-producing L. plantarum strains are able to recruit immune cells in vitro. Conclusions: The results show the ability of engineered L. plantarum to produce a functional chemotactic protein immobilized on the bacterial surface. We observed that the activity of surface-displayed CCL3Gag differed depending on the type of anchor used. The chemokine which is a part of the bacteria-based vaccine may increase the recruitment of immune cells and, thereby, enhance the reaction of the immune system to the vaccine.
MeSH term(s)	Cell Line ; Chemokine CCL3/genetics ; Chemokine CCL3/metabolism ; Chemotaxis ; Flow Cytometry ; HIV-1/metabolism ; Humans ; Lactobacillus plantarum/growth & development ; Lactobacillus plantarum/metabolism ; Microscopy, Fluorescence ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/genetics ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Vaccines, Synthetic/immunology ; gag Gene Products, Human Immunodeficiency Virus/genetics ; gag Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Chemokine CCL3 ; Recombinant Fusion Proteins ; Vaccines, Synthetic ; gag Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2015-10-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1475-2859
ISSN (online)	1475-2859
DOI	10.1186/s12934-015-0360-z
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Article ; Online: Antibody-mediated delivery of T-cell epitopes to antigen-presenting cells induce strong CD4 and CD8 T-cell responses.

Høydahl, Lene S / Frigstad, Terje / Rasmussen, Ingunn B / Øynebråten, Inger / Schjetne, Karoline W / Andersen, Jan Terje / Michaelsen, Terje E / Lunde, Elin / Bogen, Bjarne / Sandlie, Inger

Vaccine

2021 Volume 39, Issue 11, Page(s) 1583–1592

Abstract: Targeted delivery of antigen to antigen-presenting cells (APCs) enhances antigen presentation and thus, is a potent strategy for making more efficacious vaccines. This can be achieved by use of antibodies with specificity for endocytic surface molecules ... ...

Abstract	Targeted delivery of antigen to antigen-presenting cells (APCs) enhances antigen presentation and thus, is a potent strategy for making more efficacious vaccines. This can be achieved by use of antibodies with specificity for endocytic surface molecules expressed on the APC. We aimed to compare two different antibody-antigen fusion modes in their ability to induce T-cell responses; first, exchange of immunoglobulin (Ig) constant domain loops with a T-cell epitope (Troybody), and second, fusion of T-cell epitope or whole antigen to the antibody C-terminus. Although both strategies are well-established, they have not previously been compared using the same system. We found that both antibody-antigen fusion modes led to presentation of the T-cell epitope. The strength of the T-cell responses varied, however, with the most efficient Troybody inducing CD4 T-cell proliferation and cytokine secretion at 10-100-fold lower concentration than the antibodies carrying antigen fused to the C-terminus, both in vitro and after intravenous injection in mice. Furthermore, we exchanged this loop with an MHCI-restricted T-cell epitope, and the resulting antibody enabled efficient cross-presentation to CD8 T cells in vivo. Targeting of antigen to APCs by use of such antibody-antigen fusions is thus an attractive vaccination strategy for increased activation of both CD4 and CD8 peptide-specific T cells.
MeSH term(s)	Animals ; Antigen Presentation ; Antigen-Presenting Cells ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Epitopes, T-Lymphocyte ; Mice
Chemical Substances	Epitopes, T-Lymphocyte
Language	English
Publishing date	2021-02-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2021.02.012
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Zs.A 1930: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Increased generation of HIV-1 gp120-reactive CD8+ T cells by a DNA vaccine construct encoding the chemokine CCL3.

Øynebråten, Inger / Hinkula, Jorma / Fredriksen, Agnete B / Bogen, Bjarne

PloS one

2014 Volume 9, Issue 8, Page(s) e104814

Abstract: DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the ...

Abstract	DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV-1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8+ T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.
MeSH term(s)	Animals ; Base Sequence ; CD8-Positive T-Lymphocytes/immunology ; Chemokine CCL3/genetics ; DNA Primers ; Enzyme-Linked Immunosorbent Assay ; HIV Antibodies/biosynthesis ; HIV Envelope Protein gp120/immunology ; HIV-1/immunology ; Mice ; Neutralization Tests ; Polymerase Chain Reaction ; Vaccines, DNA/administration & dosage ; Vaccines, DNA/genetics ; Vaccines, DNA/immunology
Chemical Substances	Chemokine CCL3 ; DNA Primers ; HIV Antibodies ; HIV Envelope Protein gp120 ; Vaccines, DNA
Language	English
Publishing date	2014-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0104814
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Article: Coupling of HIV-1 Antigen to the Selective Autophagy Receptor SQSTM1/p62 Promotes T-Cell-Mediated Immunity.

Andersen, Aram Nikolai / Landsverk, Ole Jørgen / Simonsen, Anne / Bogen, Bjarne / Corthay, Alexandre / Øynebråten, Inger

Frontiers in immunology

2016 Volume 7, Page(s) 167

Abstract: Vaccines aiming to promote T-cell-mediated immune responses have so far showed limited efficacy, and there is a need for novel strategies. Studies indicate that autophagy plays an inherent role in antigen processing and presentation for CD4(+) and CD8(+) ...

Abstract	Vaccines aiming to promote T-cell-mediated immune responses have so far showed limited efficacy, and there is a need for novel strategies. Studies indicate that autophagy plays an inherent role in antigen processing and presentation for CD4(+) and CD8(+) T cells. Here, we report a novel vaccine strategy based on fusion of antigen to the selective autophagy receptor sequestosome 1 (SQSTM1)/p62. We hypothesized that redirection of vaccine antigen from proteasomal degradation into the autophagy pathway would increase the generation of antigen-specific T cells. A hybrid vaccine construct was designed in which the antigen is fused to the C-terminus of p62, a signaling hub, and a receptor that naturally delivers ubiquitinated cargo for autophagic degradation. Fusion of the human immunodeficiency virus-1 antigen Gagp24 to p62 resulted in efficient antigen delivery into the autophagy pathway. Intradermal immunization of mice revealed that, in comparison to Gagp24 delivered alone, fusion to p62 enhanced the number of Gagp24-specific interferon-γ-producing T cells, including CD8(+) T cells. The strategy may also have the potential to modulate the antigenic peptide repertoire. Because p62 and autophagy are highly conserved between species, we anticipate this strategy to be a candidate for the development of T-cell-based vaccines in humans.
Language	English
Publishing date	2016
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2016.00167
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