Laureates raised knowledge of the development of the immune system to a new level
Immunologists Frederick W. Alt (73) of Harvard Medical School and David G. Schatz (64) of Yale School of Medicine are to receive the 2023 Paul Ehrlich and Ludwig Darmstaedter Prize, as the Scientific Council of the Paul Ehrlich Foundation announced today. The two researchers are being acknowledged for their discovery of molecules and mechanisms that enable our immune system to perform the astounding feat of recognizing billions of different antigens on first contact.
FRANKFURT. Both the antibodies produced by B cells and structures on the surface of T cells are able to capture antigens. Collectively, they are referred to as antigen receptors. In the first instance, their tremendous variety is thanks to different gene fragments combining at random to form functional genes. Almost 50 years ago, this principle was first demonstrated for the production of antibodies. However, the finer details of this somatic recombination remained largely in the dark until Alt and Schatz increasingly shed light on the subject. “The picture we have today of the diversification of antigen receptors in the immune system of vertebrates is above all thanks to the two prize winners," says Professor Thomas Boehm, Chairman of the Scientific Council of the Paul Ehrlich Foundation. “They have raised our knowledge of the development of the immune system to a new level."
Antigen receptors are proteins consisting of constant and variable parts. In each antibody, for example, two heavy and two light chains are joined together in a Y-shape. Which antigen an antibody can recognize depends on the variable parts in the arms of the Y. In each of our B cells, an antibody with different claws matures during its development in the bone marrow. In total, our body can build approximately ten billion different antibodies, although it has only about 20,000 protein blueprints in the form of genes. It achieves this by means of an extraordinarily daring procedure that makes cutting up and re-assembling the genetic information DNA on certain chromosomes of maturing lymphocytes the norm.
The enzyme complex RAG1/2 discovered by David Schatz and colleagues conducts these cuts at pre-designated sites. For the formation of the variable portions of heavy antibody chains, for example, these sites are located on chromosome 14. There, they flank relatively widely spaced segments in three different regions called V (for variable), D (for diversity), and J (for joining). RAG1/2 conducts cuts at a randomly selected segment from each of these regions for each antibody. Subsequently, DNA repair enzymes assemble a VDJ gene to encode a heavy chain variable region. Frederick Alt discovered the repair enzymes that work together to join the ends of the cut-out segments. In the next step of B cell maturation, the light chains are formed in a similar way, but only a VJ recombination occurs there in this case.
The RAG enzymes do not, however, wander aimlessly through the cell nucleus of immature lymphocytes. On the contrary, they draw the chromatin filaments together, in which the DNA is coiled up in a space-saving way, temporarily and again and again to form V(D)J recombination centers. There, they perform chromatin scanning. In this process, a chromatin loop, which can be more than one million DNA letters long, passes through the recombination center so that widely separated sections of text can be reliably linked together. The loop extrusion mechanism of V(D)J recombination elucidated by Frederick Alt elegantly explains how these loops are created and pulled through the recombination center.
Frederick Alt made further decisive contributions to the understanding of antigen receptor diversity. For example, he succeeded in showing that combinatorial diversity is increased many-fold by the enzymatic insertion of very short random DNA sequences, called N-nucleotides, at the interfaces of the gene segments to be joined. In B cells, antibody diversity is further potentiated by the phenomenon of somatic hypermutation. In this process, the normal rate of mutations affecting only one DNA letter is increased millions of times in the regions of the V segments by an enzyme. Alt, Schatz, and others showed how this enzyme performs its work with pinpoint accuracy. They thus provided a framework for solving the question of how B cells can take advantage of the enormous mutational capacity of AID for antibody maturation without running the risk of suffering tumor-inducing mutations.
Without the recombination-activating enzyme complex RAG1/2, the diversification of antigen receptors is impossible, the maturation of the lymphocytes is disrupted, and a severe immune defect is the consequence. It is all the more remarkable that this molecule apparently originates from a jumping gene – a transposon. These are selfish DNA parasites that crept into our genome at some point and can move from one place to another as jumping genes. Because of their uncontrolled distribution, they can be involved in the development of disease. RAG1/2, however, according to David Schatz's findings, descends from a transposon that all jawed vertebrates, including us humans, tamed for their own purposes very early in evolution. To prevent it from jumping on, they had to fix it in the genome. Schatz has shown which biochemical mechanisms enable this fixation. He was also able, on the basis of structural biological studies in an ancient invertebrate RAG gene to reproduce the act of transposition over several stages. He is thus giving science a fascinating look back at a revolutionary process at the beginning of vertebrate evolution: the development of the adaptive immune system in addition to already existing innate immunity. Building on this view from basic research, translational research will be able to open up new therapeutic perspectives for diseases in which our immune system plays a crucial role.
Frederick W. Alt (Website) is the Charles A. Janeway Professor of Pediatrics and Director of the Program in Cellular and Molecular Medicine at Boston Children's Hospital, a Howard Hughes Medical Institute Investigator, and a Professor of Genetics at Harvard Medical School.
David G. Schatz (Website) is Professor of Molecular Biophysics and Biochemistry at Yale University and Chairperson of the Department of Immunobiology at Yale School of Medicine.
Photos of the award winners are available for use at www.paul-ehrlich-stiftung.de.
Background information with the title “Protected by a tamed parasite"
The prizes will be awarded by the Chairman of the Scientific Council of the Paul Ehrlich Foundation on 14 March 2023 at 5 p.m. in Frankfurt's Paulskirche. We kindly ask you to take this into consideration when planning your diary. Please do not hesitate to contact us if you have any questions.
The Paul Ehrlich and Ludwig Darmstaedter Prize is Germany's most renowned medical award, endowed with 120,000 euros. It is traditionally awarded on Paul Ehrlich's birthday, 14 March, in Frankfurt's Paulskirche. It honours scientists who have made special contributions in areas of research represented by Paul Ehrlich's achievements, namely in immunology, cancer research, haematology, microbiology and chemotherapy. The prize, which has been awarded since 1952, is funded by the Federal Ministry of Health, the German Association of Research-based Pharmaceutical Companies (Verband Forschender Arzneimittelhersteller e.V.) and by earmarked donations from the following companies, foundations and institutions: Else Kröner-Fresenius-Foundation, Sanofi-Aventis Deutschland GmbH, C.H. Boehringer Sohn AG & Co. KG, Biotest AG, Hans und Wolfgang Schleussner-Foundation, Fresenius SE & Co. KGaA, F. Hoffmann-LaRoche Ltd., Grünenthal Group, Janssen-Cilag GmbH, Merck KGaA, Bayer AG, Georg von Holtzbrinck GmbH & Co.KG, AbbVie Deutschland GmbH & Co. KG., B. Metzler seel. Sohn & Co KGaA. The award winners are selected by the Scientific Council of the Paul Ehrlich Foundation. A list of the members of the Scientific Council is available on the website of the Paul Ehrlich Foundation.
The Paul Ehrlich Foundation is a legally dependent foundation administered in trust by the Association of Friends and Benefactors of Goethe University. Honorary President of the Foundation, which was established in 1929 by Hedwig Ehrlich, is Professor Dr Katja Becker, President of the German Research Foundation, who also appoints the elected members of the Foundation Council and the Board of Trustees. The Chairman of the Scientific Council of the Paul Ehrlich Foundation is Professor Dr Thomas Boehm, Director at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg, and the Chairman of the Board of Trustees is Professor Dr Jochen Maas, Managing Director Research & Development, Sanofi-Aventis Deutschland GmbH. In his function as Chairman of the Association of Friends and Benefactors of Goethe University, Prof. Dr Wilhelm Bender is also a member of the Scientific Council of the Paul Ehrlich Foundation. The President of Goethe University is in this capacity also a member of the Board of Trustees.
Heart and COVID-19 study at University Hospital Frankfurt/Goethe University Frankfurt reveals long-term effects after SARS-CoV-2 infection
The research team led by Dr Valentina Puntmann and Professor Eike Nagel from University Hospital Frankfurt and Goethe University Frankfurt followed up around 350 study participants without previously known heart problems who had recovered from a SARS-CoV-2 infection. They found that over half of them still reported heart symptoms almost a year later, such as exercise intolerance, tachycardia and chest pain. According to the study, these symptoms can be attributed to mild but persistent cardiac inflammation. Pronounced structural heart disease is not a characteristic of the syndrome. (Nature Medicine, DOI 10.1038/s41591-022-02000-0).
FRANKFURT. After recovering from a SARS-CoV-2 infection, many people complain of persistent heart complaints, such as poor exercise tolerance, palpitations or chest pain, even if the infection was mild and there were no known heart problems in the past. Earlier studies, predominantly among young, physically fit individuals, were already able to show that mild cardiac inflammation can occur after COVID-19. However, the underlying cause of persistent symptoms, and whether this changes over time, was unknown.
A team of medical scientists led by Dr Valentina Puntmann and Professor Eike Nagel from the Institute for Experimental and Translational Cardiovascular Imaging at University Hospital Frankfurt followed up 346 people – half of them women – between the age of 18 and 77 years, in each case around four and eleven months after the documented SARS-CoV-2 infection. For this purpose, the team analysed the study participants' blood, conducted heart MRIs, and recorded and graded their symptoms using standardised questionnaires.
The result: 73 percent reported heart problems at the beginning of the study and in 57 percent these symptoms persisted 11 months after the SARS-CoV-2 infection. The research team measured mild but persistent heart inflammation that was not accompanied by structural changes in the heart. Blood levels of troponin – a protein that enters the blood when the heart muscle is damaged – were also unremarkable.
Dr Puntmann, who led the Impression COVID&Heart Study, explains: “The patients' symptoms match our medical findings. It is important to note that although triggered by the SARS-CoV-2 virus, the post-COVID cardiac inflammatory involvement differs considerably from classic viral myocarditis. Extensive damage of the heart muscle leading to structural heart changes or impaired function are not characteristic at this stage of disease evolution." The clinical picture is more reminiscent, she says, of the findings in chronic diffuse inflammatory syndromes such as autoimmune conditions. “Although most likely driven by a virus-triggered autoimmune process, a lot more research is needed in order to understand the underlying pathophysiology. Similarly, the long-term effects of cardiac inflammation following a mild COVID infection need to be clarified in future studies."
Because the study is restricted to a selected group of individuals who took part because they had symptoms, the prevalence of findings cannot be extrapolated to the population as a whole. Bayer AG, the German Heart Foundation and the German Centre for Cardiovascular Research supported the study.
Publication: Valentina O. Puntmann, Simon Martin, Anastasia Shchendrygina, Jedrzej Hoffmann, Mame Madjiguène Ka, Eleni Giokoglu, Byambasuren Vanchin, Niels Holm, Argyro Karyou, Gerald S. Laux, Christophe Arendt, Philipp De Leuw, Kai Zacharowski, Yascha Khodamoradi, Maria J. G. T. Vehreschild, Gernot Rohde, Andreas M. Zeiher, Thomas J. Vogl, Carsten Schwenke, Eike Nagel Long-term cardiac pathology in individuals with mild initial COVID-19 illness. Nature Medicine (2022) https://www.nature.com/articles/s41591-022-02000-0
Background: The heart after COVID-19 – Long-term damage from COVID-19 does not always heal without treatment (Forschung Frankfurt 1.2021) https://www.forschung-frankfurt.uni-frankfurt.de/108536066.pdf
Picture download: https://www.uni-frankfurt.de/124064044
Caption: Visualisation of heart inflammation by means of MRI: cardiologist Dr Valentina Puntmann monitors a study participant at the Institute for Experimental and Translational Cardiovascular Imaging at University Hospital Frankfurt.
Dr Valentina Puntmann
University Hospital Frankfurt / Goethe University Frankfurt
Institute for Experimental and Translational Cardiovascular Imaging
Goethe University Frankfurt is currently hosting the first “EXPLORE" summer school, giving international students the opportunity to work on real astrophysical data.
FRANKFURT. They had to wait several months until their first “real" meeting could take place. Now they finally get to meet in person – 13 students from Frankfurt's partner city Toronto and 22 of their fellow students at Goethe University Frankfurt are joining a summer school on astrophysics. “It is very nice to finally have everyone come together. The students put so much effort in and came up with great results", says Prof. Laura Sagunski from the Institute for Theoretical Physics, who realised the project together with Prof. Jürgen Schaffner-Bielich and their colleagues at York University in Canada. Already during the last semester, the young people teamed up in self-organised groups to work on real physical data and research questions about Dark Matter. The innovative international teaching project called “EXPLORE: EXPeriential Learning Opportunity through Research and Exchange" enables them to learn about physics hands-on while also experiencing modern international research collaborations. Sagunski emphasizes: “By having them work together, we also want to strengthen the students' competences in intercultural communication and their ability to work in heterogeneous teams."
On Monday, the first EXPLORE summer school was opened at the Frankfurt Institute for Advanced Studies on Campus Riedberg. Frankfurt's mayor Dr. Nargess Eskandari-Grünberg, who recently visited Toronto herself, welcomed the students warmly: “It is of special importance to me that Frankfurt will be further strengthened as a research location. In times where scientific findings are being questioned, it is particularly important that researchers communicate beyond borders. That young people from Toronto and Frankfurt conduct research on such an exciting topic together makes me especially happy."
Next, Prof. Luciano Rezzolla gave a keynote on the first images of Black Holes. “It's great to see how motivated the young generation of scientists is," he says. “Therefore, I am delighted to be able to ideologically and financially support this project through the research cluster ELEMENTS."
A week full of interesting workshops and talks awaits the students, accompanied by cultural and sportive activities: They will take a stand up paddling tour on the river Main as well as explore Frankfurt on a guided tour.
Prof. Dr. Laura Sagunski
Institute for Theoretical Physics
Goethe University Frankfurt
+49 69 798 47888
Picture download: https://www.uni-frankfurt.de/123514666
Caption: Frankfurt's mayor Dr. Nargess Eskandari-Grünberg and organiser Prof. Laura Sagunski from Goethe University (front middle) with participants and lecturers of the EXPLORE summer school (Photo: Uwe Dettmar)
Antigen binding does not trigger any structural changes in T-cell receptors – Signal transduction probably occurs after receptor enrichment
T cells are our immune system's customised tools for fighting infectious diseases and tumour cells. On their surface, these special white blood cells carry a receptor that recognises antigens. With the help of cryo-electron microscopy, biochemists and structural biologists from Goethe University Frankfurt, in collaboration the University of Oxford and the Max Planck Institute of Biophysics, were able to visualise the whole T-cell receptor complex with bound antigen at atomic resolution for the first time. Thereby they helped to understand a fundamental process which may pave the way for novel therapeutic approaches targeting severe diseases.
FRANKFURT. The immune system of vertebrates is a powerful weapon against external pathogens and cancerous cells. T cells play a curcial role in this context. They carry a special receptor called the T-cell receptor on their surface that recognises antigens – small protein fragments of bacteria, viruses and infected or cancerous body cells – which are presented by specialised immune complexes. The T-cell receptor is thus largely responsible for distinguishing between “self" and “foreign". After binding of a suitable antigen to the receptor, a signalling pathway is triggered inside the T cell that “arms" the cell for the respective task. However, how this signalling pathway is activated has remained a mystery until now – despite the fact that the T-cell receptor is one of the most extensively studied receptor protein complexes.
Many surface receptors relay signals into the interior of the cell by changing their spatial structure after ligand binding. This mechanism was so far assumed to also pertain to the T-cell receptor. Researchers led by Lukas Sušac, Christoph Thomas, and Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt, in collaboration with Simon Davis from the University of Oxford and Gerhard Hummer from the Max Planck Institute of Biophysics, have now succeeded for the first time in visualizing the structure of a membrane-bound T-cell receptor complex with bound antigen. A comparison of the antigen-bound structure captured using cryo-electron microscopy with that of a receptor without antigen provides the first clues to the activation mechanism.
For the structural analysis, the researchers chose a T-cell receptor used in immunotherapy to treat melanoma and which had been optimised for this purpose in several steps in such a way that it binds its antigen as tightly as possible. A particular challenge on the way to structure determination was to isolate the whole antigen receptor assembly consisting of eleven different subunits from the cell membrane. “Until recently, nobody believed that it would be possible at all to extract such a large membrane protein complex in a stable form from the membrane," says Tampé.
Once they had successfully achieved this, the researchers used a trick to fish those receptors out of the preparation that had survived the process and were still functional: due to the strong interaction between the receptor complex and the antigen, they were able to “fish" one of the most medically important immune receptor complexes. The subsequent images collected at the cryo-electron microscope delivered groundbreaking insights into how the T-cell receptor works, as Tampé summarises: “On the basis of our structural analysis, we were able to show how the T-cell receptor assembles and recognises antigens and hypothesise how signal transduction is triggered after antigen binding." According to their results, the big surprise is that there is evidently no significant change in the receptor's spatial structure after antigen binding, as this was practically the same both with and without an antigen.
The remaining question is how antigen
binding could instead lead to T-cell activation. The co-receptor CD8 is known
to approach the T-cell receptor after antigen binding and to stimulate the
transfer of phosphate groups to its intracellular part. The researchers assume
that this leads to the formation of structures which exclude enzymes that
cleave off phosphate groups (phosphatases). If these phosphatases are missing,
the phosphate groups remain stable at the T-cell receptor and can trigger the
next step of the signalling cascade. “Our structure is a blueprint for future
studies on T-cell activation," Tampé is convinced. “In addition, it's an important
stimulus for employing the T-cell receptor in a therapeutic context for treating
infections, cancer, and autoimmune diseases."
Publication: Lukas Sušac, Mai T. Vuong, Christoph Thomas, Sören von Bülow, Caitlin O'Brien-Ball, Ana Mafalda Santos, Ricardo A. Fernandes, Gerhard Hummer, Robert Tampé, Simon J. Davis: Structure of a fully assembled tumor-specific T-cell receptor ligated by pMHC. Cell (2022) 185, Aug 18 https://doi.org/10.1016/j.cell.2022.07.010
Picture download: https://www.uni-frankfurt.de/123390758
Caption: The cryo-EM structure of the fully assembled T-cell receptor (TCR) complex with a tumor-associated peptide/MHC ligand provides important insights into the biology of TCR signaling. These insights into the nature of TCR assembly and the unusual cell membrane architecture reveal the basis of antigen recognition and receptor signaling.
Professor Robert Tampé
Collaborative Research Centre CRC 1507 – Protein Assemblies and Machineries in Cell Membranes
Institute of Biochemistry, Biocenter
Goethe University Frankfurt
Tel.: +49 69 798-29475
New international study generates insights into the inner workings of the adaptive immune response
How do killer T cells recognise cells in the body that have been infected by viruses? Matter foreign to the body is presented on the surface of these cells as antigens that act as a kind of road sign. A network of accessory proteins – the chaperones – ensure that this sign retains its stability over time. Researchers at Goethe University have now reached a comprehensive understanding of this essential cellular quality control process. Their account of the structural and mechanistic basis of chaperone networks has just appeared in the prestigious science journal Nature Communications. These new findings could be harbingers of progress in areas such as vaccine development.
FRANKFURT. Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defence reaction, specialised cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognise that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.
At this point, antigen processing comes into play. The process can be compared to making a road sign. The molecular barcode is “processed" or assembled in the cell – in the endoplasmic reticulum, to be exact. Special molecules are used in its making, the MHC class I molecules. They are loaded with information about the virus invader in a molecular machine, the peptide loading complex (PLC). This information consists of peptides, fragments of the protein foreign to the body. These fragments also contain epitopes, the molecular segments that elicit a specific immune response. During the loading process, an MHC I-peptide epitope complex thus forms, and this is the road sign that is then transported to the surface of the cell and presented in a readily accessible form to the killer T cells – we could almost say that it is handed to them on a silver platter. The chaperones, special accessory proteins that assist the correct folding of proteins with complex structures in cells, also play a significant role.
The chaperones that support antigen processing are calreticulin, ERp57, and tapasin. But how do they work together? And how important are they for antigen processing? An answer has now been supplied by a study carried out by Goethe University Frankfurt and the University of Oxford and published in Nature Communications. “With this study, we have achieved a breakthrough in our understanding of cellular quality control," says Professor Robert Tampé, Director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic underlying this quality control process as follows: “The MHC I-peptide epitope complex, the road sign, needs to be exceptionally stable, and for quite a long time, because the adaptive immune response does not start instantly. It needs 3 to 5 days to get going." So, the sign must not collapse after one day; that would be disastrous, as the immune defence cells would then fail to detect cells infected by a virus. This would mean that they would not destroy these cells and the virus would be able to continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumour cell: the threat would remain undetected. It is imperative, therefore, that a quality control system is in place.
As the study shows, the chaperones are central process components: they give the road sign the long-term stability it must have by making a strict selection. By rejecting the short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. The chaperones have different tasks in this selection process that is so important for the adaptive immune response, Tampé says: “Tapasin acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERp57, in contrast, are deployed universally." This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell surface and perform their role of guiding the killer T cells to the infected or mutated cell.
In what directions does the study point? “We now better understand
which peptides are loaded and how this occurs now. We can also more reliably
predict the dominant peptide epitopes, in other words the stable peptide
epitopes that will be selected by the chaperone network." Tampé hopes that the
new findings will prove useful for developing future vaccines against virus variants.
They could also facilitate progress on future tumour therapies. “Both topics
are directly linked. But the applications in tumour therapy are certainly more
complex and more for the long term."
Publication: Alexander Domnick, Christian Winter, Lukas Sušac, Leon Hennecke, Mario Hensen, Nicole Zitzmann, Simon Trowitzsch, Christoph Thomas, Robert Tampé: “Molecular basis of MHC I quality control in the peptide loading complex" Nature Communications 2022, 13:4701 https://doi.org/10.1038/s41467-022-32384-z
An image to download (copyrights Christoph Thomas & Robert Tampé): https://www.uni-frankfurt.de/123213123
Caption: The mechanism of MHC I assembly, epitope editing and quality control within the peptide loading complex (PLC). The fully assembled PLC machinery of antigen processing is formed by the antigen transport complex TAP1/2, the chaperones calreticulin, ERp57, and tapasin, and the heterodimeric MHC I (heavy and light chain in teal and green, respectively).
Institute of Biochemistry
Goethe University Frankfurt
Prof. Dr Robert Tampé
Tel: +49 (0)69 79829475