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Researchers from Goethe University Frankfurt, the Max von Pettenkofer Institute and Hannover Medical School are shedding light on the molecular players in the MHC-I loading complex
As part of the immune system, dendritic cells are essential for fighting body cells that have degenerated or are infected with a virus. They trigger an immune response by presenting protein fragments, for example of viruses, to T cells. In so doing, they activate the latter so that these recognize the fragments as foreign. Certain membrane proteins, MHC-I molecules, enable this process within dendritic cells. Researchers at Goethe University Frankfurt and its partner institutes have now identified further interaction partners of the protein complex responsible for loading MHC-I molecules in dendritic cells.
The specific or acquired immune system of vertebrates is a powerful weapon against pathogens and pathologically altered body cells. Here, T cells play a special role. After activation, they can systematically kill off target cells that have degenerated or are infected with a virus. They carry a receptor on their surface that recognizes small protein fragments – antigens – presented to them by specialized immune cells, including the highly efficient dendritic cells. These are phagocytes (scavenger cells) that patrol through the body in search of infected or degenerated cells, ingest them and degrade them inside a membrane vesicle. During this process, antigens are produced that enable the dendritic cells to bind to MHC-I receptors and then present them on the cell surface.
The antigenic MHC-I molecules remain stable for several days. During this time, their purpose is to activate immature (naïve) T cells and transform them into potent killer cells (cytotoxic T cells). Thanks to this “armoring function", dendritic cells constitute a ray of hope for personalized immunotherapy. With the participation of Dr. Christian Schölz from the Max von Pettenkofer Institute in Munich as well as Professor Reinhold Förster and Professor Ulrich Kalinke from Hannover Medical School, a team led by Professor Robert Tampé from Goethe University Frankfurt has now been able to show that the protein complex responsible for loading MHC-I molecules in dendritic cells is organized in supramolecular assemblies for particularly efficient antigen presentation.
Like all surface proteins, MHC-I molecules are incorporated into the membrane of the intracellular endoplasmic reticulum (ER) during synthesis. The ER is a system of tubules and sacs inside the cell, in which the MHC-I molecules are loaded with antigens carried there via a transporter called TAP.
Small vesicles with the loaded MHC-I molecules bud off from the endoplasmic reticulum, migrate to the cell membrane and fuse with it so that they appear on the cell surface and can interact with T cells. “All body cells with a nucleus present their own antigens to the immune system," Tampé explains, “but dendritic cells are the ones that present the antigens of other cells on MHC-I best of all and in this way are able to arm T cells." This is because dendritic cells have an ER with a particularly extensive network of tubules and sacs.
For their experiments, the researchers examined dendritic cells in an early stage of cell development, known as progenitor cells, allowing them to develop first into immature and then mature dendritic cells. In all three groups of cells, they found an antigenic peptide loading complex composed of TAP, MHC-I and three other proteins: tapasin, ERp57 and calreticulin, folding enzymes (chaperones) that help the three-dimensional structure of MHC-I to form correctly.
In the mature dendritic cells, three other proteins further enriched the loading complex: The researchers discovered VAPA and ESYT1 in close proximity, which normally appear at contact sites between the ER and other cell membranes, as well as BAP31. BAP31 occurs at ER exit sites, that is, where the vesicles with the folded proteins bud off from the ER. “This result indicates that antigen processing in dendritic cells is more efficient when the loading complex does not operate on its own but works in organized alliances," says Martina Barends, one of the first authors of the research paper.
This cooperation with the newly described partners suggests that loading of MHC-I molecules occurs at ER exit sites, which could enable the complexes to reach the cell surface particularly quickly. Moreover, loading complexes at contact sites between the ER and plasma membrane could facilitate direct transport to the cell surface. Tampé is convinced: “This would make antigen presentation far more efficient." The hope now is that these findings will help in the development of new immunization strategies and immunotherapies. “We now have a better idea of how antigens are produced in dendritic cells that can be used therapeutically," summarizes Tampé.
Publication: Martina Barends, Nicole Koller, Christian Schölz, Verónica Durán, Berislav Bosnjak, Jennifer Becker, Marius Döring, Hanna Blees, Reinhold Förster, Ulrich Kalinke, Robert Tampé: Dynamic interactome of the MHC I peptide loading complex in human dendritic cells. PNAS (2023) https://doi.org/10.1073/pnas.2219790120
Professor Robert Tampé
CRC 1507 – Protein Assemblies and Machineries in Cell Membranes (https:/sfb1507.de)
Institute for Biochemistry, Biocenter
Goethe University Frankfurt, Germany
Tel.: +49 69 798-29475
CRC 1507: https://sfb1507.de
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, firstname.lastname@example.org.
Researchers at Goethe University Frankfurt are examining how tumors reprogram their environment
For solid tumors to grow efficiently, they generally need the help of non-transformed, endogenous cells around them. Through the communication of these cells between each other, networks form in the tumor's environment which stimulate growth. With the support of the Wilhelm Sander Foundation, researchers at Goethe University Frankfurt have now examined such networks. In the process, they discovered that these networks are very resistant to intervention, but the team also succeeded in identifying possible weak points.
Tumors consist of both the actual, malignant cancer cells and healthy, non-transformed cells in the immediate environment. These include, among other things, the endogenous scavenger cells of the immune system, called macrophages, as well as types of cells that form connective tissue, such as fibroblasts. Both macrophages and fibroblasts normally contribute to keeping tissue in its original healthy state and to restoring its structure after minor or major damage. These capabilities also play an important role in defending the body against the proliferation and spread of cancer cells.
However, cancer cells have developed strategies to reprogram both macrophages and fibroblasts into tumor-promoting cells. In this process, the fibroblasts are altered in such a way that they change the tissue structure so that it helps the tumor cells to survive and spread. For example, if metastases form in the lung, the fibroblasts in the lung are activated first. Macrophages secrete growth and survival factors, which the tumors use, for example, to give themselves a better supply of nutrients and oxygen.
It has long been assumed in cancer research that the deactivation of specific, non-transformed types of cells might be enough for therapy to be successful. However, despite the promising results achieved in research such strategies have so far hardly been successful in the treatment of patients.
A research team led by Professor Andreas Weigert and Professor Bernhard Brüne from Goethe University Frankfurt has now identified possible reasons for this. For their analyses, the researchers used genetically modified mice that spontaneously develop tumors in their breast tissue. Through further genetic modifications, a fat-like molecule produced by the macrophages and released into the tumor environment, the hormone prostaglandin E2, was deactivated in the mammary carcinoma of these mice. Prostaglandin E2 was previously believed – on the basis of cell culture experiments – to have above all tumor-promoting properties. As expected, deactivating prostaglandin E2 also inhibited the growth of mammary carcinoma in the mice. To the surprise of the research team, however, tissue analyses showed that the fibroblasts divided extensively and were activated, and at the same time more metastases developed in the lungs of the mice.
In further trials, the transcriptome of the fibroblasts was analyzed, that is, all the genes read from the genome at that point in time. The researchers were able to show that prostaglandin E2 keeps the fibroblasts in mammary carcinoma in an inactive state by means of a previously unknown signaling pathway, which explains why removing the molecule in the mice led to increased metastasis. The process is evidently similar in humans: Fibroblasts activated in a similar way were also found in the breast tumors of some patients, and these patients were far less likely to survive.
In the course of their histological study of mammary carcinoma, the researchers also encountered a subgroup of macrophages which, similar to fibroblasts, produce parts of the extracellular matrix (the connective tissue between the cells) – above all collagens. Such macrophages, called fibrocytes, were already known from fibrotic disorders (pathological proliferation of connective tissue) of the lung, but their role in tumors was unclear.
That is why the researchers in Frankfurt, together with Professor Rajkumar Savai from the Max Planck Institute for Heart and Lung Research in Bad Nauheim, examined the role of fibrocytes in lung tumors by systematically deactivating them during tumor growth. By means of single-cell sequencing, they were able to corroborate, among other things, that these cells are a key population which coordinates both the growth of the tumor cells and their supply with blood vessels as well as the tumor-promoting activation of other macrophage subtypes.
“The results of our studies illustrate that there are many types of cells in the tumor microenvironment that promote tumor survival, growth and spread in a similar way. The tumor uses central molecular hubs through which it simultaneously reprograms various endogenous cells into tumor promoters. If we want to fight cancer effectively, we need to advance the detection and therapeutic use of such hubs," says Weigert, summarizing the study results, which were published in the renowned journals Cancer Research and Nature Communications. Identifying such hubs will be a research priority for the participating laboratories in the future.
1) E. Strack, P.A. Rolfe, A.F. Fink, K. Bankov, T. Schmid, C. Solbach, R. Savai, W. Sha, L. Pradel, S. Hartmann, B. Brüne, A. Weigert. Identification of tumor-associated macrophage subsets that are associated with breast cancer prognosis. Clin Transl Med (2020), 10:e239. https://doi.org/10.1002/ctm2.239
2) E. Elwakeel, M. Brüggemann, J. Wagih, O. Lityagina, M.A.F. Elewa, Y. Han, T. Froemel, R. Popp, A.M. Nicolas, Y. Schreiber, E. Gradhand, D. Thomas, R. Nüsing, J. Steinmetz-Späh, R. Savai, E. Fokas, I. Fleming, F.R. Greten, K. Zarnack, B. Brüne, A. Weigert. Disruption of prostaglandin E2 signaling in cancer-associated fibroblasts limits mammary carcinoma growth but promotes metastasis. Cancer Res. (2022), 82(7):1380-1395. https://doi.org/10.1158/0008-5472.can-21-2116
3) A. Weigert, X. Zheng, A. Nenzel, K. Turkowski, S. Günther, E. Strack, E. SiraitFischer, E. Elwakeel, I.M. Kur, V.S. Nikam, C. Valasarajan, H. Winter, A. Wissgott, R. Voswinkel, F. Grimminger, B. Brüne, W. Seeger, S. Savai Pullamsetti, R. Savai. Fibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system. Nat Commun. (2022), 13:6078 https://doi.org/10.1038/s41467-022-33458-8
Picture download: https://www.uni-frankfurt.de/139734297
Caption: Tissue section of a lung tumor showing different cells in the tumor microenvironment: macrophages (red), collagen-producing macrophages or fibrocytes (yellow), fibroblasts (green). Photo: Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt
Professor Andreas Weigert
Professor for Biochemistry of Innate Immunity
Institute of Biochemistry I
Faculty of Medicine
Goethe University Frankfurt
60590 Frankfurt am Main
Tel.: +49 (0) 69 6301 4593
Editor: Markus Bernards, PhD, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, email@example.com.
Together with cooperation partners, researchers from Goethe University Frankfurt are analyzing knowledge gaps and making recommendations
Science does not take a deep enough look at chemicals in the environment as one of the causes of the decline in biodiversity. Forty scientists in the RobustNature research network of Goethe University Frankfurt and collaborating institutes have corroborated this in a study that has now been published in the journal “Nature Ecology and Evolution". The researchers regard an interdisciplinary approach as a new opportunity to better understand biodiversity loss in order to be able to take more efficient countermeasures. To this end, they are studying the interactions between chemical pollution and biodiversity loss.
Declining biodiversity threatens the very basis of human life. Science contends that there are many reasons for this decline. However, while much research is being conducted into the connection between species decline on the one hand and loss of habitats, invasion by non-native species or climate change on the other, science is giving less attention to the impact of chemicals on biodiversity. A recent study by a team of researchers led by Professor Henner Hollert, Dr. Francisco Sylvester and Fabian Weichert from Goethe University Frankfurt corroborates this.
The team has analyzed in depth the scientific literature on this topic from 1990 to 2021. According to their analysis, the very many research papers on environmental pollution through chemicals were published in only a small number of highly specialized ecotoxicological journals, in which papers on biodiversity loss are only occasionally found. “This suggests that the field is highly encapsulated, which is in stark contrast to publication behavior in relation to other causes of global biodiversity loss," says Henner Hollert. “Research on the environmental impact of chemicals is still mostly dissociated from the assessment of biodiversity loss."
The authors call for a stronger interdisciplinary focus in research so that the impacts of chemical substances on biodiversity can be better understood and mitigated. What makes the researchers optimistic here is the fact that there have been many methodological advances in ecotoxicology and ecology in recent years. For example, with the help of state-of-the-art chemical and effect-based analytics as well as big data science it is possible to detect thousands of known and unknown substances in environmental samples at the same time. In addition, there are technologies for remote environmental monitoring, for example with satellites, as well as computer models for predicting the ecological risks of chemicals and methods for determining biodiversity with the help of environmental DNA.
However, the scientists also see quite considerable challenges despite the interdisciplinary approach. For example, basic data are often lacking; each area under study has specific characteristics; the processes at ecosystem scale are complex. To meet these challenges, the researchers have made 16 recommendations. They suggest, for example, obligating industry to make relevant data public. Or they propose developing ecological test models that cover not only individual organisms but also populations, communities or even entire ecosystems.
The RobustNature research network is examining the robustness and resilience of nature-society systems in the developing Anthropocene and specifically the interaction of chemical pollution and biodiversity loss. To address important questions related to human-ecosystem dynamics, RobustNature has established interdisciplinary collaboration with partners from Germany and abroad. https://www.robustnature.de/en/Partners:
Francisco Sylvester, Fabian G. Weichert, Verónica L. Lozano, Ksenia J. Groh, Miklós Bálint, Lisa Baumann, Claus Bässler, Werner Brack, Barbara Brandl, Joachim Curtius, Paul Dierkes, Petra Döll, Ingo Ebersberger, Sotirios Fragkostefanakis, Eric J. N. Helfrich, Thomas Hickler, Sarah Johann, Jonas Jourdan, Sven Klimpel, Helge Kminek, Florencia Liquin, Darrel Möllendorf, Thomas Müller, Jörg Oehlmann, Richard Ottermanns, Steffen U. Pauls, Meike Piepenbring, Jakob Pfefferle, Gerrit Jasper Schenk, J.F. Scheepens, Martin Scheringer, Sabrina Schiwy, Antje Schlottmann, Flurina Schneider, Lisa M. Schulte, Maria Schulze-Sylvester, Ernst Stelzer, Frederic Strobl, Andrea Sundermann, Klement Tockner, Tobias Tröger, Andreas Vilcinskas, Carolin Völker, Ricarda Winkelmann, Henner Hollert: Better integration of chemical pollution research will further our understanding of biodiversity loss. Nature Ecology and Evolution (2023) http://dx.doi.org/10.1038/s41559-023-02117-6
Picture download: https://www.uni-frankfurt.de/138808301
Professor Henner Hollert
Institute of Ecology, Diversity and Evolution
Goethe University Frankfurt
and Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Schmallenberg
and LOEWE Center for Translational Biodiversity Genomics (LOEWE‐TBG), Frankfurt
Tel.: +49 (0)69 798-42171
Twitter: @hhollert @goetheuni @LOEWE_TBG @fraunhofer_IME @isoewikom @senckenberg @UFZ_de @SAFE_Frankfurt @RWTH @USask_INTL @ETH @ETH_en @Stockholm_Uni
Editor: Markus Bernards, PhD, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, firstname.lastname@example.org
Goethe University Frankfurt signs cooperation agreement with United Nations Population Fund (UNFPA) for forensic "Identifications in Mexico" project.
Goethe University Frankfurt entered into a cooperation agreement with the United Nations Population Fund (UNFPA) in Mexico to assist the Mexican government in identifying the country's more than 110,000 officially disappeared. At 55,000, the official figure of unidentified decedents is also staggering. The Comisión Nacional de los Derechos Humanos, Mexico's national human rights commission, has called the current situation as a forensic crisis and an enormous burden on civil society.
Although the Mexican government is increasingly relying on international cooperation and assistance in recent years to help identify unidentified decedents, and significant progress has been made (including the construction of regional identification centers), identification remains a significant challenge. One partner is UNFPA, whose Mexican branch is a member of the “Identifications in Mexico" project (partially funded by Germany's Federal Foreign Office), which supports the Comisión Nacional de Búsqueda (CNB) search commission's national identification policy. One of the project's workplans comprises Goethe University Frankfurt's collaboration with Mexican institutions and universities.
The signing ceremony was attended by Cecilia Villanueva Bracho, Mexican Consul General to the city of Frankfurt; Goethe University President Prof. Enrico Schleiff; the Deputy Head of UNFPA Mexico, Iván Castellanos; the Director of Goethe University's Institute of Forensic Medicine, Prof. Dr. Marcel Verhoff: and UNFPA Project Head Maximilian Murck. The goal of the cooperation agreement between UNFPA and the Institute of Forensic Medicine is to offer families certainty about the whereabouts of their loved ones.
Specifically, the cooperation aims to develop pragmatic approaches to identify more deceased persons within a shorter period of time, including by means of:
Goethe University President Prof. Dr. Enrico Schleiff emphasized the humanitarian obligation to support the Mexican government in restoring the identity of unidentified decedents, adding that the relatives of the disappeared deserve to have certainty of their loved ones' fate. Schleiff welcomed the cooperation agreement, which allows the work done to date by Frankfurt's forensic experts in identifying Mexico's disappeared to be continued. He explicitly thanked UNFPA for its support of the "Identifications in Mexico" project, as well as all scientists and doctors involved.
Iván Castellanos, deputy head of UNFPA Mexico, emphasized that every person has the right to their identity, pointing to the important measures the Mexican government has initiated in recent years to strengthen its institutions in the search for the disappeared, as well as to the reforms passed to improve the identification of unidentified decedents. The government for the first time invited the United Nations Committee on Enforced Disappearances (CED) in 2021, he said, also expressing its compromise with the disappeared.
For his part, Prof. Dr. Marcel Verhoff, director of Goethe University's Institute of Forensic Medicine, pointed out that the Frankfurt-based institute had already worked with the University of Guadalajara in the introduction of a master degree in forensic science, and in the analysis of genetic samples, autopsies and excavations in Mexico. The new agreement will further strengthen academic collaboration, he said, allowing both institutions to benefit from one another, adding that the knowledge exchange will be realized both in scientific projects as well as practical identification work.
Maximilian Murck, who heads the UNFPA project, said that while identifying the dead is not an easy task, it is not an impossible one either, adding that it is important to work out common solutions and to make visible the successes of cooperation in this difficult context. One example is the introduction of fingerprint matching technology in several Mexican states – an initiative coordinated by the CNB. Murck expressed his gratitude to Goethe University as well as the Mexican institutions for their support and trust.
Regarding the cooperation agreement signed between Goethe University and UNFPA, Cecilia Villanueva Bracho, Mexico's consul general in Frankfurt, stressed: "The Mexican government supports this project that contributes to the cooperation between Mexico and Germany in the field of forensic medicine. It also serves to strengthen institutions by enabling us to better address contemporary priorities in the fields of security, crime control and prevention. The collaboration comprises the exchange of knowledge and best practices to promote governmental and academic institutions and develop technical capacities."
Image for download: www.uni-frankfurt.de/139269528
Caption (from left to right): Cecilia Villanueva Bracho, Mexico's consul general in Frankfurt; Goethe University President Prof. Dr. Enrico Schleiff; Prof. Dr. Marcel Verhoff, Director of the Institute of Forensic Medicine, and PD Dr. Christoph Birnhuber.
Editor: Dr. Dirk Frank, Press Officer / Deputy Head of the PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-13753, email@example.com
$250,000 for US research stay for the only awardee from Europe
Biochemist and structural biologist Prof. Robert Tampé of Goethe University Frankfurt has received a research fellowship worth $250,000 (EUR 230,000). He was granted Columbia University's "Schaefer Scholar Award," bestowed annually on scientists for outstanding academic achievements in human physiology. One of Prof. Tampé's research projects will be supported by $200,000 during a visiting fellowship at Columbia University; he will also receive $50,000 in discretionary funding. The prize was awarded at a ceremony in New York on June 21st, 2023.
Professor Katrina Armstrong, Chief Executive Officer of Columbia University Irving Medical Center and the university's Vice President for Health and Biomedical Sciences, congratulated Prof. Robert Tampé on the award: "We are pleased to offer you this opportunity to strengthen and expand your research. Dedicated researchers like you are absolutely necessary to further scientific discovery and medical innovation. Congratulations for this well-deserved honor, and best wishes for your continued success. We look forward to welcoming you to Columbia!"
Together with his collaborative partner, Prof. Filippo Mancia of the Department of Physiology and Cellular Physics at Columbia University, Tampé will pursue a research project in New York to elucidate transport mechanisms within the cell that are essential for triggering an immune response. His research focuses on the endoplasmic reticulum, a complex membrane system within the cell, which, among others, produces membrane proteins that are transported to the cell's outer envelope, where they are presented to the immune system as antigens and can trigger an immune response. Tampé will study a protein complex central to this process, called the peptide loading complex (PLC), which is the target of many pathogens and cancer cells that subvert the immune response in this way. The research could result in new ways to boost the immune system against pathogens or cancer.
Image download: https://www.uni-frankfurt.de/139045243
PLC_c_ChristophThomas_RobertTampe.jpg : Structure and biogenesis of the antigen processing machinery, i.e. a dynamic assembly of transport, folding and receptor complexes responsible for the adaptive immune recognition of infected or malignant cells. Illustrations: Christoph Thomas, Robert Tampé
Tampe_Robert_c_UweDettmar.jpg: Prof. Dr. Robert Tampé, Goethe University Frankfurt. Photo: Uwe Dettmar
Professor Robert Tampé
Institute of Biochemistry, Biocenter Goethe University Frankfurt, Germany
Tel: +49 (0)69 798-29475
Twitter-Handles: @goetheuni @Columbia @tampe_lab
Editor: Markus Bernards, PhD, Science Editor, PR & Communication Office, Tel: +49 (0) 69 798-12498, firstname.lastname@example.org.