24 results on '"Schild, Hansjorg"'
Search Results
2. Transient Lymph Node Immune Activation by Hydrolysable Polycarbonate Nanogels
- Author
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Czysch, Christian, Medina-Montano, Carolina, Zhong, Zifu, Fuchs, Alexander, Stickdorn, Judith, Winterwerber, Pia, Schmitt, Sascha, Deswarte, Kim, Raabe, Marco, Scherger, Maximilian, Combes, Francis, De Vrieze, Jana, Kasmi, Sabah, Sandners, Niek N., Lienenklaus, Stefan, Koynov, Kaloian, Raeder, Hans-Joachim, Lambrecht, Bart N., David, Sunil A., Bros, Matthias, Schild, Hansjorg, Grabbe, Stephan, De Geest, Bruno G., Nuhn, Lutz, Czysch, Christian, Medina-Montano, Carolina, Zhong, Zifu, Fuchs, Alexander, Stickdorn, Judith, Winterwerber, Pia, Schmitt, Sascha, Deswarte, Kim, Raabe, Marco, Scherger, Maximilian, Combes, Francis, De Vrieze, Jana, Kasmi, Sabah, Sandners, Niek N., Lienenklaus, Stefan, Koynov, Kaloian, Raeder, Hans-Joachim, Lambrecht, Bart N., David, Sunil A., Bros, Matthias, Schild, Hansjorg, Grabbe, Stephan, De Geest, Bruno G., and Nuhn, Lutz
- Abstract
The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline-type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vivo. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate-based nanogels may also be of great importance for clinical translation.
- Published
- 2022
3. [FoxP3.sup.+] regulatory T cells essentially contribute to peripheral [CD8.sup.+] T-cell tolerance induced by steady-state dendritic cells
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Schildknecht, Anita, Brauer, Sabine, Brenner, Corinne, Lahl, Katharina, Schild, Hansjorg, Sparwasser, Tim, Probst, Hans Christian, and van den Broek, Maries
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Dendritic cells -- Physiological aspects ,Dendritic cells -- Research ,Immune response -- Physiological aspects ,Immune response -- Research ,T cells -- Physiological aspects ,T cells -- Research ,Science and technology - Abstract
Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigen-presenting steady-state dendritic cells efficiently induce peripheral tolerance. We previously showed that dendritic-cell--induced tolerance is a T-cell--intrinsic process that depends on coinhibitory molecules such as programmed death-1. Here we specifically analyze the involvement of [FoxP3.sup.+] regulatory T cells, which are known to be important for maintenance of self-tolerance. We show that antigen presentation by steady-state dendritic cells failed to induce peripheral tolerance in the absence of [FoxP3.sup.+] regulatory T cells but induced protective [CD8.sup.+] T-cell--mediated immunity instead. Regulatory T-cell--depleted mice had massively increased numbers of dendritic cells in lymph nodes. Dendritic cells isolated from mice without regulatory T cells had upregulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggesting that regulatory T cells contribute to peripheral tolerance by keeping the dendritic cells in an immature state. Using blocking antibodies, we demonstrate that CTLA-4 but not IL-10 is necessary for control of dendritic cells by regulatory T cells. Treg | tolerance | DC | [CD8.sup.+] T cells www.pnas.org/cgi/doi/10.1073/pnas.0910620107
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- 2010
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4. Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition
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Nicholls, Sarah, Piper, Karen P., Mohammed, Fiyaz, Dafforn, Timothy R., Tenzer, Stefan, Salim, Mahboob, Mahendra, Premini, Craddock, Charles, van Endert, Peter, Schild, Hansjorg, Cobbold, Mark, Engelhard, Victor H., Moss, Paul A.H., and Willcox, Benjamin E.
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Genetic polymorphisms -- Research ,Histocompatibility antigens -- Genetic aspects ,Histocompatibility antigens -- Research ,HLA histocompatibility antigens -- Genetic aspects ,HLA histocompatibility antigens -- Research ,Major histocompatibility complex -- Physiological aspects ,Major histocompatibility complex -- Research ,T cells -- Physiological aspects ,T cells -- Research ,Science and technology - Abstract
T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-[1.sup.H] versus HA-[1.sup.R]) in the HMHA1 gene. The HA-[1.sup.H] peptide is restricted by HLA-A2 and is immunogenic in HA-[1.sup.R/R] into HA-[1.sup.H] transplants, while HA-[1.sup.R] has been suggested to be a 'null allele' in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-[1.sup.R] variant. To understand these findings, we determined the structure of an HLA-A2-HA-[1.sup.H] complex to 1.3[Angstrom] resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-[1.sup.H]-specific T-cells bound HA-[1.sup.H] peptide with moderate affinity but failed to bind HA-[1.sup.R], indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition. graft-versus-leukemia | stem cell transplantation | major histocompatibility complex
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- 2009
5. Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses
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Osterloh, Philipp, Linkemann, Kathrin, Tenzer, Stefan, Rammensee, Hans-Georg, Radsak, Markus P., Busch, Dirk H., and Schild, Hansjorg
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Immune response -- Research ,T cells -- Research ,Science and technology - Abstract
Differences in the cleavage specificities of constitutive proteasomes and immunoproteasomes significantly affect the generation of MHC class I ligands and therefore the activation of CD8-positive T cells. Based on these findings, we investigated whether proteasomal specificity also influences CD8-positive T cells during thymic selection by peptides derived from self proteins. We find that one of the self peptides responsible for positive selection of ovalbumin-specific OT-1 T cells, which is derived from the f-actin capping protein (Cp[alpha]1), is efficiently generated only by immunoproteasomes. Furthermore, OT-1 mice backcrossed onto low molecular mass protein 7 (LMP7)-deficient mice show a 50% reduction of OT-1 cells. This deficiency is also observed after transfer of BM from OT-1 mice in LMP7-deficient mice and can be corrected by the injection of the Cp[alpha]1 peptide. Interestingly, WT and LMP7-deficient mice mount comparable immune responses to the ovalbumin-derived epitope SIINFEKL. However, their cytotoxic T lymphocytes (CTL) differ in the use of T cell receptor V[beta] genes. CTL derived from WT mice use V[beta]8 or V[beta]5 (the latter is also used by OT-1 cells), whereas SIINFEKL-specific CTL from LMP7-deficient mice are exclusively V[beta]8-positive. Taken together, our experiments provide strong evidence that proteasomal specificity shapes the repertoire of T cells participating in antigen-specific immune responses. selection | T cell repertoire
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- 2006
6. Cleavage motifs of the yeast 20S proteasome beta subunits deduced from digests of enolase 1
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Nussbaum, Alexander K., Dick, Tobias P., Keilhotz, Wieland, Schirle, Markus, Stevanovic, Stefan, Dietz, Klaus, Heinemeyer, Wolfgang, Groll, Michael, Wolf, Dieter H., Huber, Robert, Rammensee, Hans-Georg, and Schild, Hansjorg
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Yeast -- Genetic aspects ,Amino acids -- Separation ,Science and technology - Abstract
The 436-amino acid protein enolase 1 from yeast was degraded in vitro by purified wild-type and mutant yeast 20S proteasome particles. Analysis of the cleavage products at different times revealed a processive degradation mechanism and a length distribution of fragments ranging from 3 to 25 amino acids with an average length of 7 to 8 amino acids. Surprisingly, the average fragment length was very similar between wild-type and mutant 20S proteasomes with reduced numbers of active sites. This implies that the fragment length is not influenced by the distance between the active sites, as previously postulated. A detailed analysis of the cleavages also allowed the identification of certain amino acid characteristics in positions flanking the cleavage site that guide the selection of the P1 residues by the three active [Beta] subunits. Because yeast and mammalian proteasomes are highly homologous, similar cleavage motifs might be used by mammalian proteasomes. Therefore, our data provide a basis for predicting proteasomal degradation products from which peptides are sampled by major histocompatibility complex class I molecules for presentation to cytotoxic T cells.
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- 1998
7. Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands
- Author
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Dick, Tobias P., Ruppert, Thomas, Groettrup, Marcus, Kloetzel, Peter M., Kuehn, Lothar, Koszinowski, Ulrich H., Stevanovic, Stefan, Schild, Hansjorg, and Rammensee, Hans-Georg
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Proteases -- Research ,Major histocompatibility complex -- Research ,Ligands (Biochemistry) -- Research ,Scission (Chemistry) -- Research ,Biological sciences - Abstract
The gamma-interferon inducible PA28 protein complex, or 11S regulator, which is composed of two homologous subunit forming a hexa- or heptameric ring structure, is known to associate with the 20S proteasome particle. The kinetics of product generation by 20S proteasomes with and without PA28 is studied. Results indicate that the PA28 regulator significantly alters the cleavage mechanism of the proteasome and optimizes the generation of dominant T cell epitopes.
- Published
- 1996
8. The nature of major histocompatibility complex recognition by gamma delta T cells
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Schild, Hansjorg, Mavaddat, Nasim, Litzenberger, Christa, Ehrich, Elliot W., Davis, Mark M., Bluestone, Jeffrey A., Matis, Louis, Draper, Rockford K., and Yueh-hsiu Chien
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Major histocompatibility complex -- Research ,T cells -- Analysis ,Antigenic determinants -- Research ,Cellular immunity -- Research ,Biological sciences - Abstract
The topology of MHC recognition in gamma-delta T cells is unique and differs from the mechanism involved in alpha-beta T cell recognition. Class I and Class II antigen processing does not activate gamma-delta T cell clones LBK5 and G8, and peptides do not induce specificity. The surface expression of ligands on stimulator cells is crucial for G8 reactivity.
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- 1994
9. Low affinity interaction of peptide-MHC complexes with T cell receptors
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Matsui, Kiyoshi, Boniface, J. Jay, Reay, Philip A., Schild, Hansjorg, Fazekas de St. Groth, Barbara, and Davis, Mark M.
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T cells -- Receptors ,Antigen-antibody reactions -- Research ,Antigen receptors, T cell -- Research ,Major histocompatibility complex -- Research ,Science and technology ,Research - Abstract
The interaction of antigen-specific T cell receptors (TCRs) with their ligands, peptides bound to molecules of the major histocompatibility complex (MHC), is central to most immune responses, yet little is known about its chemical characteristics. The binding to T cells of a labeled monoclonal antibody to the TCR was inhibited by soluble class II MHC heterodimers complexed to different peptides. Inhibition was both peptide- and TCR-specific and of low affinity, with a [K.sub.D] = 4 x [10.sup.-5] to 6 x [10.sup.-5] M, orders of magnitude weaker than comparable antibody-antigen interactions. This finding is consistent with the scanning nature of T cell recognition and suggests that antigen-independent adhesion precedes TCR engagement., THE T CELL RECEPTOR POLYPEPTIDES occur as either αβ or λ[unkeyable] heterodimers in close association with the monomorphie CD3 polypeptides on the surface of T cells [1]. Similar to antibodies, [...]
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- 1991
10. A role for the proteasome regulator PA28 alpha in antigen presentation
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Groettrup, Marcus, Soza, Andrea, Eggers, Maren, Kuehn, Lothar, Dick, Tobias P., Schild, Hansjorg, Rammensee, Hans-Georg, Koszinowski, Ulrich H., and Kloetzel, Peter-M.
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- 1996
11. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells
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Rotzschke, Olaf, Falk, Kirsten, Deres, Karl, Schild, Hansjorg, Norda, Maria, Metzger, Jorg, Jung, Gunther, and Rammensee, Hans-Georg
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Peptides -- Physiological aspects ,T cells -- Physiological aspects ,Cell-mediated cytotoxicity -- Research ,Viruses -- Physiological aspects ,Major histocompatibility complex -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Published
- 1990
12. Limit of T cell tolerance to self proteins by peptide presentation
- Author
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Schild, Hansjorg, Rotzschke, Olaf, Kalbacher, Hubert, and Rammensee, Hans-Georg
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T cells -- Research ,Immunological tolerance -- Research ,Science and technology ,Research - Abstract
Limit of T Cell Tolerance to Self Proteins by Peptide Presentation SELF TOLERANCE IN THE IMMUNE system is established by elimination of self-reactive T lymphocytes during thymic differentiation [1]. The [...]
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- 1990
13. Autocatalytic cleavage of Clostridium difficile toxin B
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Reineke, Jessica, Tenzer, Stefan, Rupnik, Maja, Koschinski, Andreas, Hasselmayer, Oliver, Schrattenholz, Andre, Schild, Hansjorg, and von Eichel-Streiber, Christoph
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Jessica Reineke [1, 6]; Stefan Tenzer [2, 6]; Maja Rupnik [3]; Andreas Koschinski [4]; Oliver Hasselmayer [1]; André Schrattenholz [5]; Hansjörg Schild (corresponding author) [2]; Christoph von Eichel-Streiber (corresponding [...]
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- 2007
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14. Perfect use of imperfection
- Author
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Schild, Hansjorg and Rammensee, Hans-Georg
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Hansjörg Schild (corresponding author) [1]; Hans-Georg Rammensee [1] Every production process, be it industrial or cellular, aims at high efficiency. To achieve this end, the management must choose between [...]
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- 2000
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15. In vivo priming of virus-specific cytotoxic T lymphocytes with synthetic lipopeptide vaccine
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Deres, Karl, Schild, Hansjorg, Wiesmuller, Karl-Heinz, Jung, Gunther, and Rammensee, Hans-Georg
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Immune system -- Research ,T cells -- Research ,Lipoproteins -- Research ,Peptides -- Research ,Vaccines -- Research ,Immunization -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Immunity to an organism that causes disease is a complex phenomenon involving many types of cells of the immune system. Cytotoxic T cells, a subset of lymphocytes, can recognize a cell containing a foreign molecule and destroy the cell. The T cells recognize a portion of the foreign molecule along with host molecules known as major histocompatibility antigens. Since T cells recognize only a portion of the foreign molecule, it was hoped that peptides that are identical to that segment and are synthesized in the laboratory could be used to stimulate the immune system to respond. Although this artificial stimulation works in helper T cells, which are T cells involved in the production of antibodies, synthetic peptides do not stimulate cytotoxic, or killer, T cells. A peptide present in a structural protein of a virus that causes influenza was shown to stimulate and activate cytotoxic T cells when it was attached to a lipoprotein, a molecule consisting of fatty acids and protein. The mechanism of activation may involve the ability of the peptide to enter the cytoplasm of the cell, or to associate with certain major histocompatibility antigens, of which there are many, or for the complex to be inserted into the cell membrane. Peptides are being developed for vaccines. However, many different peptides from the immunogenic proteins of infectious organisms may have to be used in any given vaccine to ensure that the peptides will combine with certain host major histocompatibility antigens and will activate the immune response of cytotoxic T cells.
- Published
- 1989
16. Immunostimulating capacities of stabilized RNA molecules
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Scheel, Birgit, primary, Braedel, Sybilla, additional, Probst, Jochen, additional, Carralot, Jean-Philippe, additional, Wagner, Hermann, additional, Schild, Hansjorg, additional, Jung, Günther, additional, Rammensee, Hans-Georg, additional, and Pascolo, Steve, additional
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- 2004
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17. Quantitative aspects of T cell activation—peptide generation and editing by MHC class I molecules
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Stevanovic, Stefan, primary and Schild, Hansjorg, additional
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- 1999
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18. Substrate Specificity of Cathepsins D and E Determined by N-Terminal and C-terminal Sequencing of Peptide Pools
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Arnold, Daniele, primary, Keilholz, Wieland, additional, Schild, Hansjorg, additional, Dumrese, Tilman, additional, Stevanovic, Stefan, additional, and Rammensee, Hans-Georg, additional
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- 1997
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19. An essential role for tripeptidyl peptidase in the generation of an MHC class I epitope.
- Author
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Seifert, Ulrike, Maranon, Concepcion, Shmueli, Ayelet, Desoutter, Jean-Francois, Wesoloski, Lisa, Janek, Katharina, Henklein, Peter, Diescher, Susanne, Andrieu, Muriel, de la Salle, Henri, Weinschenk, Toni, Schild, Hansjorg, Laderach, Diego, Galy, Anne, Haas, Gaby, Kloetzel, Peter-M., Reiss, Yuval, and Hosmalin, Anne
- Subjects
PEPTIDES ,MAJOR histocompatibility complex ,DENDRITIC cells - Abstract
Most of the peptides presented by major histocompatibility complex (MHC) class I molecules require processing by proteasomes. Tripeptidyl peptidase II (TPPII), an aminopeptidase with endoproteolytic activity, may also have a role in antigen processing. Here, we analyzed the processing and presentation of the immunodominant human immunodeficiency virus epitope HIV-Nef(73-82) in human dendritic cells. We found that inhibition of proteasome activity did not impair Nef(73-82) epitope presentation. In contrast, specific inhibition of TPPII led to a reduction of Nef(73-82) epitope presentation. We propose that TPPII can act in combination with or independent of the proteasome system and can generate epitopes that evade generation by the proteasome-system. [ABSTRACT FROM AUTHOR]
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- 2003
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20. The nature of major histocompatibility complex recognition by gammadelta T cells.
- Author
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Schild, Hansjorg and Mavaddat, Nasim
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T cells , *MAJOR histocompatibility complex - Abstract
Analyzes the major histocompatibility complex (MHC) recognition properties of the gammadelta T cell clones. Activation; Epitope mapping; Defects in the MHC class I and class II peptide loading pathway.
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- 1994
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21. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome.
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Alberti, Simon, Demand, Jens, Esser, Claudia, Emmerich, Niels, Schild, Hansjorg, and Hohfeld, Jorg
- Abstract
BAG-1 is a ubiquitin domain protein that links the molecular chaperones Hsc70 and Hsp70 to the proteasome. During proteasomal sorting BAG-1 can cooperate with another co-chaperone, the carboxyl terminus of Hsc70-interacting protein CHIP. CHIP was recently identified as a Hsp70- and Hsp90-associated ubiquitin ligase that labels chaperone-presented proteins with the degradation marker ubiquitin. Here we show that BAG-1 itself is a substrate of the CHIP ubiquitin ligase in vitro and in vivo. CHIP mediates attachment of ubiquitin moieties to BAG-1 in conjunction with ubiquitin-conjugating enzymes of the Ubc4/5 family. Ubiquitylation of BAG-1 is strongly stimulated when a ternary Hsp70.BAG-1.CHIP complex is formed. Complex formation results in the attachment of an atypical polyubiquitin chain to BAG-1, in which the individual ubiquitin moieties are linked through lysine 11. The noncanonical polyubiquitin chain does not induce the degradation of BAG-1, but it stimulates a degradation-independent association of the co-chaperone with the proteasome. Remarkably, this stimulating activity depends on the simultaneous presentation of the integrated ubiquitin-like domain of BAG-1. Our data thus reveal a cooperative recognition of sorting signals at the proteolytic complex. Attachment of polyubiquitin chains to delivery factors may represent a novel mechanism to regulate protein sorting to the proteasome.
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- 2002
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22. IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma.
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Bohm, Livia, Maxeiner, Joachim, Meyer-Martin, Helen, Reuter, Sebastian, Finotto, Susetta, Klein, Matthias, Schild, Hansjorg, Schmitt, Edgar, Bopp, Tobias, and Taube, Christian
- Subjects
- *
INTERLEUKIN-10 , *T cells , *ALLERGENS , *IMMUNOTHERAPY , *ASTHMA treatment , *ALLERGIES , *INFLAMMATION - Abstract
Human studies demonstrated that allergen-specific immunotherapy (IT) represents an effective treatment for allergic diseases. IT involves repeated administration of the sensitizing allergen, indicating a crucial contribution of T cells to its medicinal benefit. However, the underlying mechanisms of IT, especially in a chronic disease, are far from being definitive. In the current study, we sought to elucidate the suppressive mechanisms of IT in a mouse model of chronic allergic asthma. OVA-sensitized mice were challenged with OVA or PBS for 4 wk. After development of chronic airway inflammation, mice received OVA-specific IT or placebo alternately to airway challenge for 3 wk. To analyze the T cell-mediated mechanisms underlying IT in vivo, we elaborated the role of T-bet-expressing Thl cells, T cell-derived IL-10, and Ag-specific thymic as well as peripherally induced Foxp3+ regulatory T (Treg) cells. IT ameliorated airway hyperresponsiveness and airway inflammation in a chronic asthma model. Of note, IT even resulted in a regression of structural changes in the airways following chronic inhaled allergen exposure. Concomitantly, IT induced Thl cells, Foxp3+, and IL-10-producing Treg cells. Detailed analyses revealed that thymic Treg cells crucially contribute to the effectiveness of IT by promoting IL-10 production in Foxp3-negative T cells. Together with the peripherally induced Agspecific Foxp3+ Treg cells, thymic Foxp3+ Treg cells orchestrate the curative mechanisms of IT. Taken together, we demonstrate that IT is effective in a chronic allergic disease and dependent on IL-10 and thymic as well as peripherally induced Ag-specific Treg cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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23. Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling.
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Bug, Stefanie, Wirths, Stefan, Radsak, Markus P., Schild, Hansjorg, Stein, Pamela, André, Maya C., Muller, Martin R., Malenke, Elke, Wiesner, Tina, Märklin, Melanie, Frick, Julia-Stefanie, Handgretinger, Rupert, Rammensee, Hans-Georg, Kanz, Lothar, and Kopp, Hans-Georg
- Subjects
- *
HOMEOSTASIS , *NEUTROPHILS , *BONE marrow , *NEUTROPENIA , *PROGENITOR cells - Abstract
Polymorphonuclear neutrophil granulocytes (neutrophils) are tightly controlled by an incompletely understood homeostatic feedback loop adjusting the marrow's supply to peripheral needs. Although it has long been known that marrow cellularity is inversely correlated with G-CSF levels, the mechanism linking peripheral clearance to production remains unknown. Herein, the feedback response to antibody induced neutropenia is characterized to consist of G-CSF-dependent shifts of marrow hematopoletic progeni- tor populations including expansion of the lin-/Sca-1+c-kit+ (LSK) and granulocyte macrophage progenitor (GMP) compartments at the expense of thrombopoietic and red cell precursors. Evidence is provided that positive feedback regulation is independent from commensal germs as well as T, B, and NK cells. However, in vivo feedback is impaired in TLR4-/- and TRIF-/-, but not MyD88-/- animals. In conclusion, steady-state neutrophil homeostasis is G-CSF-dependent and regulated through pattern-recognition receptors, thereby directly linking TLR-triggering to granulopoiesis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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24. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway.
- Author
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Vabulas RM, Braedel S, Hilf N, Singh-Jasuja H, Herter S, Ahmad-Nejad P, Kirschning CJ, Da Costa C, Rammensee HG, Wagner H, and Schild H
- Subjects
- Animals, Base Sequence, Cell Line, DNA Primers, Humans, Membrane Glycoproteins genetics, Mice, Mice, Inbred C3H, Mice, Knockout, Receptors, Cell Surface genetics, Signal Transduction, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptors, Dendritic Cells immunology, Drosophila Proteins, Endoplasmic Reticulum metabolism, Heat-Shock Proteins metabolism, Membrane Glycoproteins metabolism, Receptors, Cell Surface metabolism
- Abstract
The heat shock protein Gp96 has been shown to induce specific immune responses. On one hand, this phenomenon is based on the specific interaction with CD91 that mediates endocytosis and results in major histocompatibility complex class I-restricted representation of the Gp96-associated peptides. On the other hand, Gp96 induces activation of professional antigen-presenting cells, resulting in the production of pro-inflammatory cytokines and up-regulation of costimulatory molecules by unknown mechanisms. In this study, we have analyzed the consequences of Gp96 interaction with cells expressing different Toll-like receptors (TLRs) and with bone marrow-derived dendritic cells from mice lacking functional TLR2 and/or TLR4 molecules. We find that the Gp96-TLR2/4 interaction results in activation of nuclear factor kappaB-driven reporter genes and mitogen- and stress-activated protein kinases and induces IkappaBalpha degradation. Bone marrow-derived dendritic cells of C3H/HeJ and more pronounced C3H/HeJ/TLR2(-/-) mice fail to respond to Gp96. Interestingly, activation of bone marrow-derived dendritic cells depends on endocytosis of Gp96 molecules. Our results provide, for the first time, the molecular basis for understanding the Gp96-mediated activation of antigen-presenting cells by describing the simultaneous stimulation of the innate and adaptive immune system. This feature explains the remarkable ability of Gp96 to induce specific immune responses against tumors and pathogens.
- Published
- 2002
- Full Text
- View/download PDF
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