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2. Human milk extracellular vesicles target nodes in interconnected signalling pathways that enhance oral epithelial barrier function and dampen immune responses

Author

Zonneveld, M.I., van Herwijnen, M.J.C., Fernandez-Gutierrez, Marcela, Giovanazzi, A., de Groot, A.M., Kleinjan, M., van Capel, T.M., Sijts, E.J.A.M., Taams, L.S., Garssen, J., de Jong, E., Kleerebezem, Michiel, t Hoen, E.N.M., Redegeld, F.A.M., Wauben, M.H.M., Zonneveld, M.I., van Herwijnen, M.J.C., Fernandez-Gutierrez, Marcela, Giovanazzi, A., de Groot, A.M., Kleinjan, M., van Capel, T.M., Sijts, E.J.A.M., Taams, L.S., Garssen, J., de Jong, E., Kleerebezem, Michiel, t Hoen, E.N.M., Redegeld, F.A.M., and Wauben, M.H.M.

Abstract

Maternal milk is nature’s first functional food. It plays a crucial role in the development of the infant’s gastrointestinal (GI) tract and the immune system. Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer enclosed vesicles released by cells for intercellular communication and are a component of milk. Recently, we discovered that human milk EVs contain a unique proteome compared to other milk components. Here, we show that physiological concentrations of milk EVs support epithelial barrier function by increasing cell migration via the p38 MAPK pathway. Additionally, milk EVs inhibit agonist-induced activation of endosomal Toll like receptors TLR3 and TLR9. Furthermore, milk EVs directly inhibit activation of CD4+ T cells by temporarily suppressing T cell activation without inducing tolerance. We show that milk EV proteins target key hotspots of signalling networks that can modulate cellular processes in various cell types of the GI tract.

Published
2020

3. Human milk extracellular vesicles target nodes in interconnected signalling pathways that enhance oral epithelial barrier function and dampen immune responses

Author

Celbiologie, dB&C I&I, Immunologie, dI&I RA-I&I I&I, Afd Pharmacology, Pharmacology, Zonneveld, M.I., van Herwijnen, M.J.C., Fernandez-Gutierrez, Marcela, Giovanazzi, A., de Groot, A.M., Kleinjan, M., van Capel, T.M., Sijts, E.J.A.M., Taams, L.S., Garssen, J., de Jong, E., Kleerebezem, Michiel, t Hoen, E.N.M., Redegeld, F.A.M., Wauben, M.H.M., Celbiologie, dB&C I&I, Immunologie, dI&I RA-I&I I&I, Afd Pharmacology, Pharmacology, Zonneveld, M.I., van Herwijnen, M.J.C., Fernandez-Gutierrez, Marcela, Giovanazzi, A., de Groot, A.M., Kleinjan, M., van Capel, T.M., Sijts, E.J.A.M., Taams, L.S., Garssen, J., de Jong, E., Kleerebezem, Michiel, t Hoen, E.N.M., Redegeld, F.A.M., and Wauben, M.H.M.

Published
2020

6. Identification of novel avian influenza virus derived CD8+ T-cell epitopes

Author

Reemers, S.S.N., van Haarlem, D.A., Sijts, E.J.A.M., Vervelde, L., Jansen, C.A., Strategic Infection Biology, Dep Infectieziekten Immunologie, Strategic Infection Biology, and Dep Infectieziekten Immunologie

Subjects
Viral Diseases, HEMAGGLUTININ, animal diseases, Epitopes, T-Lymphocyte, CD8-Positive T-Lymphocytes, medicine.disease_cause, Epitope, Zoonoses, INFECTION, Cytotoxic T cell, Lymphocytes, Lung, Medicine(all), Multidisciplinary, Agricultural and Biological Sciences(all), biology, virus diseases, Flow Cytometry, Infectious Diseases, CHICKEN, Medicine, Research Article, Veterinary Medicine, Science, Immune Cells, Immunology, Hemagglutinin (influenza), IMMUNITY, Major histocompatibility complex, Virus, Cell Line, Interferon-gamma, A VIRUS, MHC class I, medicine, Animals, Life Science, Biology, T-CELL RESPONSES, Influenza A Virus, H5N1 Subtype, Biochemistry, Genetics and Molecular Biology(all), MEMORY, Histocompatibility Antigens Class I, Immunity, Virology, Influenza A virus subtype H5N1, MAJOR HISTOCOMPATIBILITY COMPLEX, Influenza in Birds, biology.protein, Leukocytes, Mononuclear, Clinical Immunology, Veterinary Science, CLASS-I MOLECULE, MHC, Peptides, Chickens, CD8
Abstract

Avian influenza virus (AIV) infection is a continuing threat to both humans and poultry. Influenza virus specific CD8+ T cells are associated with protection against homologous and heterologous influenza strains. In contrast to what has been described for humans and mice, knowledge on epitope-specific CD8+ T cells in chickens is limited. Therefore, we set out to identify AIV-specific CD8+ T-cell epitopes. Epitope predictions based on anchor residues resulted in 33 candidate epitopes. MHC I inbred chickens were infected with a low pathogenic AIV strain and sacrificed at 5, 7, 10 and 14 days post infection (dpi). Lymphocytes isolated from lung, spleen and blood were stimulated ex vivo with AIV-specific pooled or individual peptides and the production of IFN gamma was determined by ELIspot. This resulted in the identification of 12 MHC B12-restricted, 3 B4-restricted and 1 B19-restricted AIV-specific CD8+ T-cell epitopes. In conclusion, we have identified novel AIV-derived CD8+ T-cell epitopes for several inbred chicken strains. This knowledge can be used to study the role of CD8+ T cells against AIV infection in a natural host for influenza, and may be important for vaccine development.

Published
2012
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10. Proteasome Immunosubunits Protect against the Development of CD8 T Cell-Mediated Autoimmune Diseases

Author

Zaiss, D.M.W., Bekker, C.P.J., Grone, A., Lie, B.A., Sijts, E.J.A.M., Strategic Infection Biology, Dep Infectieziekten Immunologie, and Dep Pathobiologie

Subjects
Proteasome Endopeptidase Complex, Immunology, Autoimmunity, CD8-Positive T-Lymphocytes, Biology, Major histocompatibility complex, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Autoimmune Diseases, Proinflammatory cytokine, Mice, Risk Factors, MHC class I, medicine, Animals, Humans, Immunology and Allergy, Cytotoxic T cell, Genetic Predisposition to Disease, Molecular Biology, Mice, Knockout, MHC class II, Cell biology, Diabetes Mellitus, Type 1, Proteasome, biology.protein, Cancer research, CD8
Abstract

Exposure of cells to inflammatory cytokines induces the expression of three proteasome immunosubunits, two of which are encoded in the MHC class II region. The induced subunits replace their constitutive homologs in newly formed “so-called” immunoproteasomes. Immunosubunit incorporation enhances the proteasome’s proteolytic activity and modifies the proteasome’s cleavage-site preferences, which improves the generation of many MHC class I-presented peptides and shapes the fine specificity of pathogen-specific CD8 T cell responses. In this article, we report on a second effect of immunoproteasome formation on CD8 T cell responses. We show that mice deficient for the immunosubunits β5i/low molecular mass polypeptide (LMP7) and β2i/multicatalytic endopeptidase complex-like–1 develop early-stage multiorgan autoimmunity following irradiation and bone marrow transplantation. Disease symptoms are caused by CD8 T cells and are transferable into immunosubunit-deficient, RAG1-deficient mice. Moreover, using the human Type 1 Diabetes Genetics Consortium MHC dataset, we identified two single nucleotide polymorphisms within the β5i/LMP7-encoding gene sequences, which were in strong linkage disequilibrium, as independent genetic risk factors for type 1 diabetes development in humans. Strikingly, these single nucleotide polymorphisms significantly enhanced the risk conferred by HLA haplotypes that were previously shown to predispose for type 1 diabetes. These data suggested that inflammation-induced immunosubunit expression in peripheral tissues constitutes a mechanism that prevents the development of CD8 T cell-mediated autoimmune diseases.

Published
2011

11. Considerations in the design of vaccines that induce CD8 T cell mediated immunity

Author

Zaiss, D.M.W., Boog, C.J.P., van Eden, W., Sijts, E.J.A.M., Strategic Infection Biology, dI&I RA-I&I I&I, and Dep Infectieziekten Immunologie

Subjects
Cellular immunity, T cell, Antigen presentation, CD8-Positive T-Lymphocytes, Biology, Antigen, Immunity, medicine, Antigen-presenting cell, Neutralizing antibody, Antigen Presentation, Vaccines, General Veterinary, General Immunology and Microbiology, Immunodominant Epitopes, Public Health, Environmental and Occupational Health, Antibodies, Neutralizing, Virology, Vaccination, Infectious Diseases, medicine.anatomical_structure, Drug Design, Immunology, biology.protein, Molecular Medicine, Immunologic Memory
Abstract

The protective capacity of many currently used vaccines is based on induction of neutralizing antibodies. Many pathogens, however, have adapted themselves in different ways to escape antibody-based immune protection. In particular, for those infections against which conventional neutralizing antibody-based vaccinations appear challenging, CD8 T-cells are considered to be promising candidates for vaccine targeting. The design of vaccines that induce robust and long-lasting protective CD8 T-cell responses however imposes new challenges, as many factors such as kinetics and efficiency of antigen-processing and presentation by antigen presenting cells, T-cell repertoire and cytokine environment during T cell priming contribute to the specificity and functionality of CD8 T-cell responses. In the following, we review the most prominent aspects that underlie CD8 T-cell induction and discuss how this knowledge may help to improve the design of efficient CD8 T-cell inducing vaccines.

Published
2010

12. Enhanced Inflammatory Potential of CD4+ T-Cells That Lack Proteasome Immunosubunit Expression, in a T-Cell Transfer-Based Colitis Model

Author

Rashid, O, Meulenbroeks, C., Gröne, A., Zaiss, D.M.W., Sijts, E.J.A.M., Rashid, O, Meulenbroeks, C., Gröne, A., Zaiss, D.M.W., and Sijts, E.J.A.M.

Abstract

Proteasomes play a fundamental role in intracellular protein degradation and therewith regulate a variety of cellular processes. Exposure of cells to (pro)inflammatory cytokines upregulates the expression of three inducible catalytic proteasome subunits, the immunosubunits, which incorporate into newly assembled proteasome complexes and alter the catalytic activity of the cellular proteasome population. Single gene-deficient mice lacking one of the three immunosubunits are resistant to dextran sulfate sodium (DSS)-induced colitis development and, likewise, inhibition of one single immunosubunit protects mice against the development of DSS-induced colitis. The observed diminished disease susceptibility has been attributed to altered cytokine production and CD4+ T-cell differentiation in the absence of immunosubunits. To further test whether the catalytic activity conferred by immunosubunits plays an essential role in CD4+ T-cell function and to distinguish between the role of immunosubunits in effector T-cells versus inflamed tissue, we used a T-cell transfer-induced colitis model. Naïve wt or immunosubunit-deficient CD4+ T-cells were adoptively transferred into RAG1−/− and immunosubunit-deficient RAG1−/− mice and colitis development was determined six weeks later. While immunosubunit expression in recipient mice had no effect on colitis development, transferred immunosubunit-deficient T- cells were more potent in inducing colitis and produced more proinflammatory IL17 than wt T-cells. Taken together, our data show that modifications in proteasome-mediated proteolysis in T-cells, conferred by lack of immunosubunit incorporation, do not attenuate but enhance CD4+ T-cell-induced inflammation.

Published
2014

13. Enhanced Inflammatory Potential of CD4+ T-Cells That Lack Proteasome Immunosubunit Expression, in a T-Cell Transfer-Based Colitis Model

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, PB SIB, Dep Infectieziekten Immunologie, Dep Pathobiologie, I&I RATIA-SIB, dI&I RA-I&I I&I, Rashid, O, Meulenbroeks, C., Gröne, A., Zaiss, D.M.W., Sijts, E.J.A.M., Risk Assessment of Toxic and Immunomodulatory Agents, Strategic Infection Biology, PB SIB, Dep Infectieziekten Immunologie, Dep Pathobiologie, I&I RATIA-SIB, dI&I RA-I&I I&I, Rashid, O, Meulenbroeks, C., Gröne, A., Zaiss, D.M.W., and Sijts, E.J.A.M.

Published
2014

18. Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

Author

Loosdregt, J. van, Fleskens, V., Fu, J., Brenkman, A.B., Bekker, C.P.J., Pals, C.E.G.M., Meerding, J., Berkers, C.R., Barbi, J., Gröne, A., Sijts, E.J.A.M., Maurice, M.M., Kalkhoven, E., Prakken, B.J., Ovaa, H., Pan, F., Zaiss, D.M.W., Coffer, P.J, Loosdregt, J. van, Fleskens, V., Fu, J., Brenkman, A.B., Bekker, C.P.J., Pals, C.E.G.M., Meerding, J., Berkers, C.R., Barbi, J., Gröne, A., Sijts, E.J.A.M., Maurice, M.M., Kalkhoven, E., Prakken, B.J., Ovaa, H., Pan, F., Zaiss, D.M.W., and Coffer, P.J

Published
2013

19. Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function

Author

Loosdregt, J. van, Fleskens, V., Tiemessen, M.M., Mokry, M., Boxtel, R. van, Meerding, J., Pals, C.E.G.M., Kurek, D., Baert, M.R., Delemarre, E.M., Gröne, A., Groot Koerkamp, M.J.A., Sijts, E.J.A.M., Nieuwenhuis, E.E.S., Maurice, M.M., Es, J.H. van, Berge, D. ten, Holstege, F.C., Staal, F.J.T., Zaiss, D.M.W., Prakken, A.B.J., Coffer, P.J, Loosdregt, J. van, Fleskens, V., Tiemessen, M.M., Mokry, M., Boxtel, R. van, Meerding, J., Pals, C.E.G.M., Kurek, D., Baert, M.R., Delemarre, E.M., Gröne, A., Groot Koerkamp, M.J.A., Sijts, E.J.A.M., Nieuwenhuis, E.E.S., Maurice, M.M., Es, J.H. van, Berge, D. ten, Holstege, F.C., Staal, F.J.T., Zaiss, D.M.W., Prakken, A.B.J., and Coffer, P.J

Published
2013

21. Pre-existing virus-specific CD8(+) T-cells provide protection against pneumovirus-induced disease in mice

Author

Strategic Infection Biology, Dep Infectieziekten Immunologie, Dep Pathobiologie, van Helden, M.J.G., van Kooten, P.J., Bekker, C.P.J., Grone, A., Topham, D.J., Easton, A.J, Boog, C.J.P., Busch, D.H., Zaiss, D.M.W., Sijts, E.J.A.M., Strategic Infection Biology, Dep Infectieziekten Immunologie, Dep Pathobiologie, van Helden, M.J.G., van Kooten, P.J., Bekker, C.P.J., Grone, A., Topham, D.J., Easton, A.J, Boog, C.J.P., Busch, D.H., Zaiss, D.M.W., and Sijts, E.J.A.M.

Published
2012

22. Identification of novel avian influenza virus derived CD8+ T cell epitopes

Author

Strategic Infection Biology, Dep Infectieziekten Immunologie, Reemers, S.S.N., van Haarlem, D.A., Sijts, E.J.A.M., Vervelde, L., Jansen, C.A., Strategic Infection Biology, Dep Infectieziekten Immunologie, Reemers, S.S.N., van Haarlem, D.A., Sijts, E.J.A.M., Vervelde, L., and Jansen, C.A.

Published
2012

25. PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I-binding peptides in vivo.

Author

Strategic Infection Biology, Dep Infectieziekten Immunologie, de Graaf, N., van Helden, M.J.G., Textoris-Taube, K., Chiba, T., Topham, D.J., Kloetzel, P.M., Zaiss, D.M.W., Sijts, E.J.A.M., Strategic Infection Biology, Dep Infectieziekten Immunologie, de Graaf, N., van Helden, M.J.G., Textoris-Taube, K., Chiba, T., Topham, D.J., Kloetzel, P.M., Zaiss, D.M.W., and Sijts, E.J.A.M.

Published
2011

30. The N-terminal flanking region of the TRP2360-368 melanoma antigen determines proteasome activator PA28 requirement for epitope liberation.

Author

Strategic Infection Biology, Dep Infectieziekten Immunologie, Textoris-Taube, K., Henklein, P., Pollmann, S., Bergann, T., Weisshoff, H., Seifert, U., Drung, I., Mugge, C., Sijts, E.J.A.M., Kloetzel, P.M., Kuckelkorn, U., Strategic Infection Biology, Dep Infectieziekten Immunologie, Textoris-Taube, K., Henklein, P., Pollmann, S., Bergann, T., Weisshoff, H., Seifert, U., Drung, I., Mugge, C., Sijts, E.J.A.M., Kloetzel, P.M., and Kuckelkorn, U.

Published
2007

34. Cloning of the MCF1233 murine leukemia virus and identification of sequences involved in viral tropism, oncogenicity and T-cell epitope formation

Author

Sijts, E.J.A.M., Leupers, C.J.M., Mengede, E.A.M., Loenen, W.A.M., Vandenelsen, P.J., and Melief, C.J.M.

Subjects
Mouse leukemia viruses -- Research, Tropisms -- Physiological aspects, Carcinogenesis -- Research, Antigenic determinants -- Physiological aspects, Business, Health care industry
Abstract

According to the authors' abstract of an article published in Virus Research, 'MCF1233 is an oncogenic C57BL-derived retrovirus of the Murine Leukemia Virus (MuLV) family, that causes T and B [...]

Published
1995

35. Immunosurveillance of Virus-induced Tumors

Author

Melief, C.J.M., primary, Vasmel, W.L.E., additional, Offringa, R., additional, Sijts, E.J.A.M., additional, Matthews, E.A., additional, Peters, P.J., additional, Meloen, R.H., additional, van der Eb, A.J., additional, and Kast, W.M., additional

Published
1989
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36. Regulation of inflammation in canine species: a role for macrophages and Hsp70

Author

Qingkang Lyu, Eden, W. van, Broere, F., Sijts, E.J.A.M., and University Utrecht

Subjects
Chemistry, Macrophage polarization, medicine, Inflammation, Canine Species, medicine.symptom, Nf κb activation, Leucinostatin, health care economics and organizations, humanities, Hsp70, Cell biology, leucinostatin, canine retinal pigment epithelial cells, NF-κB activation, canine macrophage, M1 and M2 macrophages, macrophage polarization, 030D monocyte-like cell line
Abstract

Summary This thesis can be roughly divided into two parts. In the first three chapters, we discussed and studied the role of Hsp70 in retinal pigment epithelial (RPE) cells, and the innate and adaptive immune response. We reviewed the relationship of T cell-mediated diseases and HSPs, and pointed out that the induction of Hsp70 may contribute to therapeutic tolerance (chapter 2). Then, we explored a new Hsp70 co-inducer, leucinostatin, and its role in canine RPE cells (chapter 3). Further, we studied the anti-inflammatory effects of Hsp70 in canine macrophages (chapter 4). In the last two chapters, we focus on various differently activated canine macrophage subsets originating from both primary monocytes and a monocyte-like cell line (030D cell) (chapter 5 and 6). We successfully polarized canine monocyte-derived macrophages (MDMs) into M1 and M2 cells and thoroughly characterized their features (chapter 5). Meanwhile, we demonstrated that 030D cells can be differentiated into M1 and M2 macrophages and that each subset shares the characteristics of the corresponding canine monocyte-derived macrophage subset.

Published
2021

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