University of Constance

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University of Constance

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Schliehe C.,University of Konstanz | Redaelli C.,University of Konstanz | Engelhardt S.,University of Konstanz | Fehlings M.,University of Konstanz | And 7 more authors.
Journal of Immunology | Year: 2011

The analysis of cell types involved in cross-priming of particulate Ag is essential to understand and improve immunotherapies using microparticles. In this study, we show that murine splenic dendritic cells (DCs) as well as macrophages (MΦs) are able to efficiently endocytose poly(D,L-lactate-co- glycolate) acid (PLGA) microspheres (MS) and to cross-present encapsulated Ags in the context of MHC class I molecules in vitro. A comparison of purified CD8+ and CD8- DCs indicated that both DC subtypes are able to present OVA-derived epitopes on MHC class I and II in vitro. To determine the contribution of DCs and MΦs to cross-priming of PLGA MS in vivo, DCs were depleted in transgenic CD11c-DTR mice, and MΦs were depleted by clodronate liposomes in wild-type mice before immunizing mice with OVA-encapsulated MS. Our results show that the depletion of DCs or MΦs alone only led to minor differences in the OVA-specific immune responses. However, simultaneous depletion of DCs and MΦs caused a strong reduction of primed effector cells, indicating a redundancy of both cell populations for the priming of PLGA MS-encapsulated Ag. Finally, we analyzed PLGA MS trafficking to draining lymph nodes after s.c. injection. It was evident that fluorescent particles accumulated within draining lymph nodes over time. Further analysis of PLGA MS-positive lymphatic cells revealed that mainly CD8- DCs and MΦs contained MS. Moreover, immune responses in BATF3 knockout mice lacking CD8+ DCs were normal. The results presented in this work strongly suggest that in vivo cross-priming of PLGA MS-encapsulated Ag is performed by CD8-DCs and MΦs. Copyright © 2011 by The American Association of Immunologists, Inc.

Schliehe C.,University of Konstanz | Schliehe C.,University of Hamburg | Thiry M.,University of Hamburg | Tromsdorf U.I.,University of Hamburg | And 4 more authors.
Journal of Controlled Release | Year: 2011

Biodegradable poly-(D,L-lactide-co-glycolide) microspheres (PLGA-MS) are approved as a drug delivery system in humans and represent a promising antigen delivery device for immunotherapy against cancer. Immune responses following PLGA-MS vaccination require cross-presentation of encapsulated antigen by professional antigen presenting cells (APCs). While the potential of PLGA-MS as vaccine formulations is well established, the intracellular pathway of cross-presentation following phagocytosis of PLGA-MS is still under debate. A part of the controversy stems from the difficulty in unambiguously identifying PLGA-MS within cells. Here we show a novel strategy for the efficient encapsulation of inorganic nanocrystals (NCs) into PLGA-MS as a tool to study their intracellular localization. We microencapsulated NCs as an electron dense marker to study the intracellular localization of PLGA-MS by transmission electron microscopy (TEM) and as fluorescent labels for confocal laser scanning microscopy. Using this method, we found PLGA-MS to be rapidly taken up by dendritic cells and macrophages. Co-localization with the lysosomal marker LAMP1 showed a lysosomal storage of PLGA-MS for over two days after uptake, long after the initiation of cross-presentation had occurred. Our data argue against an escape of PLGA-MS from the endosome as has previously been suggested as a mechanism to facilitate cross-presentation of PLGA-MS encapsulated antigen. © 2011 Elsevier B.V. All rights reserved.

Groettrup M.,University of Konstanz | Groettrup M.,University of Constance | Kirk C.J.,Onyx Pharmaceuticals | Basler M.,University of Konstanz | Basler M.,University of Constance
Nature Reviews Immunology | Year: 2010

When cells are stimulated with pro-inflammatory cytokines, most of their constitutively expressed proteasomes are replaced with immunoproteasomes, which increase the production of peptides for presentation on MHC class I molecules. In addition, cortical thymic epithelial cells selectively express a type of proteasome known as the thymoproteasome that is required for the positive selection of thymocytes. Here, we discuss how these specialized types of proteasome shape the T cell receptor repertoire of cytotoxic T lymphocytes and propose that immunoproteasomes have functions, in addition to antigen processing, that influence cytokine production and T cell differentiation, survival and function. We also discuss how inhibitors of immunoproteasomes can suppress undesired T cell responses in autoimmune diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Schliehe C.,University of Konstanz | Bitzer A.,University of Konstanz | van den Broek M.,University of Zürich | Groettrupa M.,University of Konstanz | Groettrupa M.,University of Constance
Journal of Virology | Year: 2012

The induction of strong CD8+ T-cell responses against infectious diseases and cancer has remained a major challenge. Depending on the source of antigen and the infectious agent, priming of CD8+ T cells requires direct and/or cross-presentation of antigenic peptides on major histocompatibility complex (MHC) class I molecules by professional antigen-presenting cells (APCs). However, both pathways show distinct preferences concerning antigen stability. Whereas direct presentation was shown to efficiently present peptides derived from rapidly degraded proteins, cross-presentation is dependent on long-lived antigen species. In this report, we analyzed the role of antigen stability on DNA vaccination and recombinant vaccinia virus (VV) infection using altered versions of the same antigen. The long-lived nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) can be targeted for degradation by N-terminal fusion to ubiquitin or, as we show here, to the ubiquitin-like modifier FAT10. Direct presentation by cells either transfected with NP-encoding plasmids or infected with recombinant VV in vitro was enhanced in the presence of short-lived antigens. In vivo, however, the highest induction of NP-specific CD8+ T-cell responses was achieved in the presence of long-lived NP. Our experiments provide evidence that targeting antigens for proteasomal degradation does not improve the immunogenicity of DNA vaccines and recombinant VVs. Rather, it is the long-lived antigen that is superior for the efficient activation of MHC class I-restricted immune responses in vivo. Hence, our results suggest a dominant role for antigen cross-priming in DNA vaccination and recombinant VV infection. © 2012, American Society for Microbiology.

Henn A.,University of Konstanz | Basler M.,University of Constance | Guillaume B.,Ludwig Institute for Cancer Research | Leist M.,University of Konstanz | And 2 more authors.
Journal of Immunology | Year: 2010

Tissue inflammation is accompanied by the cytokine-mediated replacement of constitutive proteasomes by immunoproteasomes that finally leads to an optimized generation of MHC class I restricted epitopes for Ag presentation. The brain is considered an immunoprivileged organ, where both the special anatomy as well as active tolerance mechanisms repress the development of inflammatory responses and help to prevent immunopathological damage. We analyzed the immunoproteasome expression in the brain after an infection with lymphocytic choriomeningitis virus (LCMV) and could show that LCMV-infection of mice leads to the transcriptional induction of inducible proteasome subunits in the brain. However, compared with other organs, i.p. and even intracranial infection with LCMV only led to a faint expression of mature immunoproteasome in the brain and resulted in the accumulation of immunoproteasomal precursors. By immunohistology, we could identify microglia-like cells as the main producers of immunoproteasome, whereas in astrocytes immunoproteasome expression was almost exclusively restricted to nuclei. Neither the immunoproteasome subunits low molecular mass polypeptide 2 nor multicatalytic endopeptidase complex-like-1 were detected in neurons or oligodendrocytes. In vitro studies of IFN-γ-stimulated primary astrocytes suggested that the observed accumulation of immunoproteasomal precursor complexes takes place in this cell population. Functionally, the lack of immunoproteasomes protracted and lowered the severity of LCMV-induced meningitis in LMP7-/- mice suggesting a contribution of immunoproteasomes in microglia to exacerbate immunopathological damage. We postulate a posttranslationally regulated mechanism that prevents abundant and inappropriate immunoproteasome assembly in the brain and may contribute to the protection of poorly regenerating cells of the CNS from immunopathological destruction. Copyright © 2010 by The American Association of Immunologists, Inc.

News Article | November 28, 2016

Topics range from medical imaging to analysis of authority and trust in US politics and society; €87 million in funding for an initial 4.5 years The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) is establishing 20 new Research Training Groups (RTGs) to further support early career researchers in Germany. They include three International Research Training Groups (IRTGs) with partners in the UK, New Zealand and Austria. This was decided by the responsible Grants Committee during its autumn session in Bonn. The Research Training Groups will receive funding of around 87 million euros for an initial period of four and a half years. In addition to the 20 new collaborations, the Grants Committee approved the extension of seven Research Training Groups for another four and a half years. This funding instrument enables doctoral researchers to complete their theses in a structured research and qualification programme at a high academic level. In total the DFG is currently funding 206 Research Training Groups, including 41 International Research Training Groups; the 20 new groups will commence their work in 2017. The new Research Training Groups in detail (in alphabetical order by their host universities, including the name of the applicant universities): Sketches, abstracts, notes, records, excerpts, essays, articles and glosses: all these 'small forms' of writing are an essential part of the practice of research, teaching, art and the media. The Research Training Group "The Literary and Epistemic History of Small Forms" intends to study their emergence and development, with which they are also involved in the success of prose, from antiquity to the present day. The group will also seek to understand how processes of understanding are controlled, reflected and channelled in specific media using these small forms. (Host university: Humboldt University of Berlin, Spokesperson: Professor Dr. Joseph Vogl) Imaging techniques such as ultrasound, X-rays and CT scans are well known. Medical findings are established on the basis of the image data produced in technically and mathematically complex processes. However, physicians' diagnoses are normally made on the basis of qualitative arguments, which do not make full use of the information content of image data and in particular the potential of imaging methods. The "BIOQIC - BIOphysical Quantitative Imaging Towards Clinical Diagnosis" Research Training Group will therefore study biophysical quantitative medical imaging to further develop these quantitative methods and apply them in clinical pilot studies to obtain more information from the imaging process. (Host universities: Humboldt University of Berlin and Free University of Berlin / Charité - University Hospital Berlin, Spokesperson: Professor Dr. Ingolf Sack) The Research Training Group "World Politics: The Emergence of Political Arenas and Modes of Observation in World Society" is concerned with the emergence of world politics as a type of politics in its own right. From the perspective of the theory of global society, the group aims to investigate the extent to which the emergence of world politics represents both a consequence and a precondition of the constitution of modern states. Researchers specialising in political science, sociology, history and law will collaborate to address this question. (Host university: University of Bielefeld, Spokesperson: Professor Dr. Mathias Albert) Perception, the authorship of action, emotions, and social and linguistic understanding are central cognitive phenomena. The Research Training Group "Situated Cognition - New Concepts in Investigating Core Mental Phenomena" will combine the philosophy of the mind and cognition with cognition sciences, which closely interact with cognitive neurosciences. The main aim of the group is to identify deficits in existing concepts of the human mind and further develop these concepts such as to give more attention to more recent developments in cognition sciences that are not yet adequately reflected in philosophical theory formation. (Host university: University of Bochum, Spokesperson: Professor Dr. Albert Newen; Additional applicant university: University of Osnabrück) Short-term dynamic loads such as impacts, detonations or earthquakes can cause structures to collapse. The aim of the Research Training Group "Mineral-Bonded Composites for Enhanced Structural Impact Safety" is to make existing buildings and structures more resilient through the addition of thin-layer reinforcements. With the help of new mineral-bonded materials known as composites, the researchers aim to improve the safety of people and the infrastructure essential to their lives. (Host university: Technical University of Dresden, Spokesperson: Professor Dr.-Ing. Viktor Mechtcherine) According to the World Health Organization, more than 422 million people worldwide suffer from diabetes, with approximately 3.7 million mortalities per year. In Germany, experts estimate the number of sufferers at 8 to 10 million. The German-British Research Training Group "Immunological and Cellular Strategies in Metabolic Disease (ICSMD)" aims to achieve a better understanding of the pathophysiology of type 1 and type 2 diabetes and develop strategies to halt the progress of the disease or even discover a cure. (Host university: Technical University of Dresden, Spokesperson: Professor Dr. Stefan R. Bornstein, Cooperation partner: King's College London, Great Britain) The German-Austrian Research Training Group "Resonant Self-World Relations in Ancient and Modern Socio-Religious Practices" will investigate ritual practices which generate, determine or express meaningful relations between people and the world - to other people, things, nature, self, heaven and God or the gods. The nature of these world relations, in turn, says much about a given culture and the social or gender positions which characterise it. The establishment of the group has been approved by the DFG's Grants Committee on Research Training Groups. The Austrian Science Fund (FWF) will reach a decision on co-funding at its next meeting. (Host university: University of Erfurt, Spokesperson: Professor Dr. Jörg Rüpke, Cooperation partner: University of Graz, Austria) The Research Training Group "Configurations of Cinema" understands film as a medium in constant transformation. In three working areas, 'formations', 'usages' and 'localisations', the group intends to analyse the genealogy and transformation of a wide variety of configurations of film, also in regard to the shift from cinemas to portable digital devices. The researchers will thus explore new modes of writing the history of a medium that is subject to constant change and examine film's defining features. (Host university: Goethe University of Frankfurt am Main, Spokesperson: Professor Dr. Vinzenz Hediger) How are authority and trust formed in US politics? How does this happen in American society, in religion and culture? The Research Training Group "Authority and Trust in American Culture, Society, History and Politics" intends to answer these questions. The chosen object of analysis is the USA because, due to its early democratization, egalitarian-libertarian political culture, ethnocultural heterogeneity and international hegemony, the country offers particularly fundamental insights into the problems of authority and trust in the modern age. (Host university: University of Heidelberg, Spokesperson: Professor Dr. Manfred Berg) The Research Training Group "Tip- and Laser-Based 3D-Nanofabrication in Extended Macroscopic Working Areas" will develop manufacturing methods for two-dimensional and three-dimensional structures on a nanometre scale using tip-based and laser-based techniques. The research work will primarily be based on nanopositioning and nanomeasuring machines, allowing structuring and measuring to take place on the same machine. With the aid of this equipment the researchers intend to give particular attention to larger and uneven surfaces, such as optical lenses. (Host university: Technical University of Ilmenau, Spokesperson: Professor Dr.-Ing. Eberhard Manske) Batteries are seen as key components of future technologies such as electric vehicles and energy supplies. The Research Training Group "SIMET - Simulation Mechano-Electro-Thermal Processes in Lithium-Ion Batteries" will work on numerical simulation methods for lithium-ion batteries. The researchers will address the problem in a multi-scale approach in several different orders of magnitude. As well as individual particles, they will simulate the electrode pair and the complete cell. (Host university: Karlsruhe Institute of Technology (KIT), Spokesperson: Professor Dr.-Ing. Thomas Wetzel) Patients with chronic diseases of the brain are normally treated with medication, but this is frequently associated with side effects. Neuroimplants, on the other hand, allow localised therapy, but must satisfy many requirements. The Research Training Group "Materials for Brain (M4B): Thin Film Functional Materials for Minimally Invasive Therapy of Brain Diseases" intends to study the use of nanoscale, therapeutically active coatings for implants of this type. Its aim is to achieve the controlled release of substances into the brain by means of the coating. (Host university: University of Kiel, Spokesperson: Professor Dr. Christine Selhuber-Unkel) We do not know enough about the reaction of lake ecosystems to environmental changes to be able to predict reliably whether they actually return to their original state following renaturation measures. Taking the example of Lake Constance, the Research Training Group "R3 - Responses to Biotic and Abiotic Changes, Resilience and Reversibility of Lake Ecosystems" aims to better understand the reactions of lake ecosystems to environmental changes, their resilience - the resistance of an ecosystem to disturbances - and their reversibility, in other words the ability to return to an original state following disturbance. (Host university: University of Constance, Spokesperson: Professor Dr. Frank Peeters) For many mathematical questions, approximation and dimension reduction are the most important tools for achieving simplified representation and therefore saving computing time. The Research Training Group "Mathematical Complexity Reduction (CoRe)" will approach complexity reduction in a more general sense and will also investigate when problems can be made easier to solve through embedding in higher dimensional spaces ('liftings'). The group also intends to systematically examine the influence of the costs of data collection. (Host university: University of Magdeburg, Spokesperson: Professor Dr. Sebastian Sager) One of the basic requirements for the economic success of a business is the efficient use of resources. In an increasingly networked world, several decision-makers are often involved in resource management and the amount of data available is growing. The Research Training Group "Advanced Optimization in a Networked Economy (AdONE)", based in the fields of operations research and management science, aims to develop models and processes and transfer these into software solutions designed to enable efficient use of resources through intelligent planning and control. (Host university: Technical University of Munich, Spokesperson: Professor Dr. Stefan Minner) Rapidly increasing antibiotic resistance and the growth of so-called lifestyle diseases confront humanity with enormous challenges. In the Research Training Group "Evolutionary Processes in Adaptation and Disease (RTG EvoPAD)", doctoral researchers in biology, medicine and the philosophy of science will therefore investigate adaptations and diseases by drawing on modern evolutionary research and approaches in the philosophy of science, in order to better understand them. (Host university: University of Münster, Spokesperson: Professor Dr. Joachim Kurtz) The development of metropolises prior to the age of industrialisation and globalisation has not, so far, been the subject of sufficient research. The "Pre-Modern Metropolitanism" Research Training Group intends to close this gap by investigating the establishment, impact and evolution of major urban centres from Ancient Greece and Rome to the dawn of the industrial age. (Host university: University of Regensburg, Spokesperson: Professor Dr. Jörg Oberste) Until now there have been few if any approaches to the improvement of robots that work with easily modifiable materials or handle soft tissue. In a German-New Zealand Research Training Group, doctoral researchers will investigate "Soft Tissue Robotics - Simulation-Driven Concepts and Design for Control and Automation for Robotic Devices Interacting with Soft Tissues". The aim is to further develop simulation techniques and sensors in order to enable new regulation and control technology for robots that interact with soft materials. (Host university: University of Stuttgart, Spokesperson: Professor Oliver Röhrle, Ph.D., Cooperation partner: University of Auckland, New Zealand) For many tumours there are no means of prevention, which is why they are usually diagnosed in advanced stages. It is also difficult to develop efficient therapies for tumours because there are genomic differences not only between different tumours (intertumoral) but also within a single tumour (intratumoral), which contributes to therapy resistance. The Research Training Group "Heterogeneity and Evolution in Solid Tumors (HEIST): Molecular Characterization and Therapeutic Consequences" aims to understand intra- and intertumoral heterogeneity, the evolutionary history of a tumour and the genes responsible for it in order to improve the treatment of tumours even in advanced stages. (Host university: University of Ulm, Spokesperson: Professor Dr. Thomas Seufferlein) Aberrations in what is known as the ubiquitin system in the body contribute to the development of a wide range of diseases such as cancer, neurodegenerative diseases and infectious diseases. The aim of the Research Training Group "Understanding Ubiquitylation: From Molecular Mechanisms To Disease" is therefore to understand the biochemical and pathogenic mechanisms which underlie diseases associated with the ubiquitin system. (Host university: University of Würzburg, Spokesperson: Professor Dr. Alexander Buchberger) Further information will also be provided by the spokespersons of the Research Training Groups. More details about the funding programme and the funded Research Training Groups is available at: http://www.

Hiller N.,Karlsruhe Institute of Technology | Hillenbrand S.,Karlsruhe Institute of Technology | Hofmann A.,Karlsruhe Institute of Technology | Huttel E.,Karlsruhe Institute of Technology | And 11 more authors.
IPAC 2010 - 1st International Particle Accelerator Conference | Year: 2010

A dedicated optics with a low momentum compaction factor is used at the ANKA storage ring to reduce the bunch length to generate coherent synchrotron radiation (CSR). A double sweep streak camera is employed to determine the bunch length and shape for different optics and as a function of the beam current. Measurements of the longitudinal bunch profile have been performed for many different momentum compaction factors and various bunch currents. This paper describes the set up of the streak camera experiments and compares the measured bunch lengths to theoretical expectations.

Huber E.M.,TU Munich | Basler M.,University of Konstanz | Basler M.,University of Constance | Schwab R.,University of Konstanz | And 5 more authors.
Cell | Year: 2012

Constitutive proteasomes and immunoproteasomes shape the peptide repertoire presented by major histocompatibility complex class I (MHC-I) molecules by harboring different sets of catalytically active subunits. Here, we present the crystal structures of constitutive proteasomes and immunoproteasomes from mouse in the presence and absence of the epoxyketone inhibitor PR-957 (ONX 0914) at 2.9 resolution. Based on our X-ray data, we propose a unique catalytic feature for the immunoproteasome subunit β5i/LMP7. Comparison of ligand-free and ligand-bound proteasomes reveals conformational changes in the S1 pocket of β5c/X but not β5i, thereby explaining the selectivity of PR-957 for β5i. Time-resolved structures of yeast proteasome:PR-957 complexes indicate that ligand docking to the active site occurs only via the reactive head group and the P1 side chain. Together, our results support structure-guided design of inhibitory lead structures selective for immunoproteasomes that are linked to cytokine production and diseases like cancer and autoimmune disorders. © 2012 Elsevier Inc.

Rani N.,University of Konstanz | Aichem A.,University of Constance | Schmidtke G.,University of Konstanz | Kreft S.G.,University of Konstanz | And 2 more authors.
Nature Communications | Year: 2012

FAT10 is the only ubiquitin-like modifier that can target proteins for degradation by the proteasome in a ubiquitin-independent manner. The degradation of FAT10-linked proteins by the proteasome is strongly accelerated by the ubiquitin-like-ubiquitin-associated protein NEDD8 ultimate buster-1 long (NUB1L). Here we show how FAT10 and NUB1L dock with the 26S proteasome to initiate proteolysis. We identify the 26S proteasome subunit hRpn10/S5a as the receptor for FAT10, whereas NUB1L can bind to both Rpn10 and Rpn1/S2. Unexpectedly, FAT10 and NUB1L both interact with hRpn10 via the VWA domain. FAT10 degradation in yeast shows that human Rpn10 can functionally reconstitute Rpn10-deficient yeast and that the VWA domain of hRpn10 suffices to enable FAT10 degradation. Depletion of hRpn10 causes an accumulation of FAT10-conjugates also in human cells. In conclusion, we identify the VWA domain of hRpn10 as a receptor for ubiquitin-like proteins within the 26S proteasome and elucidate how FAT10 mediates efficient proteolysis by the proteasome. © 2012 Macmillan Publishers Limited. All rights reserved.

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