Baanbrekende nieuwe behandeling leidt tot beter herstel na hersentrauma bij muizen

Onderzoekers hebben een gerichte therapie ontworpen die ontsteking in de hersenen tegengaat. De aanpak – waarbij doelgericht DNA tot in de hersenen wordt gebracht - blijkt succesvol bij muizen met een hersenletsel, beroerte of multiple sclerose

Kort & bondig:

• Onderzoekers hebben een gerichte therapie ontworpen die ontsteking in de hersenen tegengaat. De aanpak – waarbij doelgericht DNA tot in de hersenen wordt gebracht - blijkt succesvol bij muizen met een hersenletsel, beroerte of multiple sclerose. 
• De behandeling bestaat er in het aantal regulatoire T-cellen, die de anti-inflammatoire respons van het immuunsysteem reguleren, te verhogen in de hersenen.  
• Door het aantal regulerende T-cellen in de hersenen te verhogen, konden de onderzoekers het afsterven van hersenweefsel bij muizen na verwonding voorkomen en deden de muizen het beter bij cognitieve testen. 
• Voor patiënten met een traumatisch hersenletsel zijn er momenteel weinig opties om schadelijke neuroinflammatie te voorkomen. De nieuwe resultaten zijn dus erg hoopgevend. 

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Onderzoekers uit Leuven en uit het Verenigd Koninkrijk publiceren vandaag nieuwe resultaten over een therapeutische piste waarbij het immuunsysteem wordt ingezet om hersenbeschadiging te voorkomen. De samenwerking tussen professor Adrian Liston (voorheen VIB en KU Leuven en sinds enkele jaren verbonden aan het Babraham Institute in het VK) en professor Matthew Holt (verbonden aan VIB, KU Leuven en de i3S-Universiteit van Porto) leidde tot een systeem om in de hersenen het aantal gespecialiseerde ontstekingsremmende immuuncellen op te voeren om op die manier hersenontsteking en -beschadiging te beperken. De aanpak bleek alvast in muismodellen tot minder hersenschade te leiden na hersenletsel, beroerte of bij multiple sclerose. Het onderzoek wordt vandaag gepubliceerd in het tijdschrift Nature Immunology. 

Traumatisch hersenletsel, zoals veroorzaakt na een auto-ongeval of een val, is wereldwijd een belangrijke doodsoorzaak. Het kan langdurige en ernstige gevolgen hebben voor mensen die het overleven, onder de vorm van cognitieve problemen en zelfs dementie. Een belangrijke oorzaak van deze cognitieve stoornissen is de ontstekingsreactie op het letsel. Hierbij veroorzaakt zwelling van de hersenen permanente schade. Terwijl ontsteking in andere delen van het lichaam kan worden aangepakt met geneesmiddelen, is dit in de hersenen heel moeilijk door de aanwezigheid van de bloed-hersenbarrière, die voorkomt dat gewone ontstekingsremmende moleculen op de plaats van het (hersen)trauma kunnen komen.  

Prof. Liston: "Ons lichaam heeft zijn eigen ontstekingsremmende respons: regulatoire T-cellen zijn in staat om ontstekingen waar te nemen en een cocktail van natuurlijke ontstekingsremmers te produceren. Helaas zijn er maar heel weinig van deze regulerende T-cellen in de hersenen. Wij probeerden een nieuw therapeutisch middel te ontwikkelen om de hoeveelheid regulerende T-cellen in de hersenen te vergroten. Indien er voldoende regulatoire T-cellen zijn, zo redeneerden we, zouden ze de ontsteking na een letsel kunnen beheersen en de schade beperken." 

Het onderzoeksteam ontdekte dat het aantal regulerende T-cellen in de hersenen laag was door een beperkte aanvoer van het cruciale overlevingsmolecuul interleukine 2, ook bekend als IL2. Het niveau van IL2 is laag in de hersenen vergeleken met de rest van het lichaam omdat het niet doorheen de bloed-hersenbarrière kan.  

Samen bedacht het team een nieuwe therapeutische aanpak waardoor meer IL2 kan worden aangemaakt door hersencellen. De onderzoekers gebruikten een "gene delivery"-systeem op basis van een virale vector: dit systeem kan daadwerkelijk een intacte bloed-hersenbarrière passeren en het DNA afleveren dat de hersenen nodig hebben om meer IL2 aan te maken.  

Prof. Holt: "Jarenlang leek de bloed-hersenbarrière een onoverkomelijke hindernis voor de efficiënte toediening van biologische geneesmiddelen in de hersenen. Ons werk, waarbij we gebruik maken van de nieuwste virale vectortechnologie, bewijst dat dit niet langer het geval is; het is zelfs mogelijk dat de bloed-hersenbarrière onder bepaalde omstandigheden therapeutisch gunstig kan zijn, omdat ze – eenmaal op hun bestemming – het 'lekken' van geneesmiddelen naar de rest van het lichaam verhindert." 

Dankzij hun aanpak waren de onderzoekers in staat de niveaus van de overlevingsmolecule IL2 in de hersenen op te voeren tot dezelfde niveaus als in het bloed. Hierdoor kon het aantal regulerende T-cellen zich in de hersenen opbouwen, tot 10 maal hoger dan normaal. Om de doeltreffendheid van de behandeling te testen in muizen. Wat bleek? Muizen met meer IL2 hadden inderdaad minder hersenschade na een letsel en presteerden ook beter in cognitieve tests.  

Dr. Lidia Yshii, van het team aan KU Leuven, legt uit: "Toen we de hersenen van de muizen zagen na het eerste experiment, was dit een echt 'eureka-moment' - we zagen meteen dat de behandeling het letsel had verkleind."  

De onderzoekers testten ook de doeltreffendheid van hun aanpak in experimentele muismodellen voor multiple sclerose en beroerte—met succes. In een vervolgstudie, die nog aan peer review wordt onderworpen en dus nog niet gepubliceerd is, toont het onderzoeksteam ook aan dat de behandeling doeltreffend was om cognitieve achteruitgang bij ouder wordende muizen te voorkomen.  

"Door de immuunrespons in de hersenen te begrijpen en erop in te spelen, waren we in staat een gen-toedieningssysteem voor IL-2 te ontwikkelen als een potentiële behandeling voor neuro-inflammatie. Met tientallen miljoenen mensen die er elk jaar mee te maken krijgen en met bovendien weinig beschikbare behandelingsmogelijkheden, biedt onze nieuwe aanpak reële mogelijkheden om mensen in nood te helpen. We hopen dat dit systeem binnenkort aan klinische proeven zal worden onderworpen, die essentieel zullen zijn om te testen of de behandeling ook bij patiënten werkt," aldus Prof. Liston. 

Dr. Ed Needham, een neuroloog in het Addenbrooke's Hospital in het VK die geen deel uitmaakte van de studie, gaf commentaar op de klinische relevantie van deze resultaten: "Er is een dringende klinische noodzaak om behandelingen te ontwikkelen die secundair letsel kunnen voorkomen dat optreedt na een traumatisch hersenletsel. Belangrijk is dat deze behandelingen veilig zijn voor gebruik bij kritisch zieke patiënten die een hoog risico lopen op levensbedreigende infecties. De huidige ontstekingsremmende geneesmiddelen werken in op het gehele immuunsysteem en kunnen daardoor de gevoeligheid van patiënten voor dergelijke infecties vergroten. Wat deze studie zo interessant maakt is dat de behandeling niet alleen met succes de door ontsteking veroorzaakte hersenschade kan verminderen, maar dat zij dit kan doen zonder de rest van het immuunsysteem van het lichaam aan te tasten, waardoor de natuurlijke afweer die nodig is om kritieke ziekte te overleven, behouden blijft." 

The genetic underpinnings of severe staph infections

In a large collaborative effort, an international team of researchers describes a genetic mutation that predisposes individuals to severe staphylococcus infections. The research, in collaboration with the Babraham Institute, appears in the latest edition of Science.

Staphylococcus aureus is usually harmless. Many of us host colonies of this bacterium in our noses and on our skin without suffering more than the occasional rash. But some strains of staph—particularly MRSA—can turn deadly, leading to pneumonia and sepsis that claims 20,000 lives in the U.S. each year. Now a new study describes a mutation that predisposes some individuals to severe staph infection.

Babraham Institute researcher Adrian Liston collaborated with Belgian doctors Isabelle Meyts, Rik Schrijvers, and Carine Wouters, to investigate the genetic and immunological cause of the disease.

The research, published in Science, describes a mutation in the OTULIN gene in patients who suffer life-threatening staph infections. “In a collaborative effort, several unrelated patients were identified with identical severe clinical presentations and we found a common genetic cause of the disease”, says Frederik Staels, MD, and PhD student at the University of Leuven in Belgium.

"We have characterized severe Staphylococcus aureus infection at the genetic, cellular, immunological, and clinical levels," says Dr. András Spaan, a clinical microbiologist working at The Rockefeller University in New York, who was one of the coordinators of this large international effort. "By integrating these levels, we have been able to establish causality and provide clues for future pharmaceutical interventions."

The study indicated that about 30 percent of people with this OTULIN mutation develop severe disease. This risk was reduced in patients that had acquired specific anti-staph antibodies, while patients without such neutralizing antibodies remained at very high risk of developing severe infections. “This is a potential path to protecting this at-risk patients”, explains Prof Adrian Liston, “the protected patients had acquired anti-staph antibodies through natural exposure, with each exposure being a high-risk gamble for life-threatening infection. If these patients can be identified and vaccinated, the anti-staph antibodies they gain through vaccination may protect them from serious illness”.

"Studies on these disorders can act as a compass," Prof Humblet-Baron, University of Leuven, says, “They bring new mechanistic insights about the interaction between hosts and pathogens, which can also benefit the general population with better understanding about staph infection pathogenesis.”

“From a clinical point of view, this work is of great relevance to physicians confronted with patients manifesting severe, life-threatening episodes of skin and/or lung inflammation, necessitating prompt recognition and treatment,” says Prof. Wouters, pediatric rheumatologist at the University of Leuven. 

Read the paper over at Science.

Our paper discussed on RheumMadness podcast

The RheumMadness podcast scouted our paper on using machine learning and immunoprofiling to understand juvenile idiopathic arthritis. Their summary?

Future: Future implications for immunophenotyping machine learning include the diagnosis, treatment and prognosis of all rheumatologic conditions. With the increase in potential immunomodulating targeted therapies, along with the classification of disease based on those same immune targets, an exciting possibility of choosing precise individualized treatment plans for our patients exists.

In pediatric rheumatology, we are accustomed to using complicated clinical algorithms to properly diagnose and treat our patients. But is this really the most accurate system? Machine learning and immunophenotyping have the potential to turn the field inside out. 

Chances in the Tournament: As the only pediatric team in play, this team is the dark horse. However, the long-term clinical implications of this team are arguably more far-reaching than any other team in the Machine Region—and the entire tournament. Despite the small number of participants in this study, the exclusion of psoriatic and enthesitis-related JIA, and the lack of attention given to race, ethnicity and environmental factors that could potentially alter immune signatures, we still believe the strengths of this article make it a crucial one. We stand an excellent chance.

Immunophenotyping machine learning has implications for more than just anti-tumor necrosis factor response in RA, like our opponents would argue. Our study shows that its implications stretch far beyond one diagnosis or two therapy choices. In fact, pediatric rheumatologists have just begun to pave the way for better classifying patients in the adult world as well. Could eight subtypes of RA actually exist, and you just don’t know it yet? Immunophenotyping through machine learning could be the disrupter you’ve been waiting for. This study can go all the way.

Listen to the podcast here

Manipulating brain Tregs to protect against neuropathology

From the GlobalImmuno Talks 20222:

New understanding of cell stability with potential to improve immune cell therapies

Researchers identify the origin of potentially dangerous unstable cells

Key points:

• Researchers have identified the origin of unstable cells, with potential to improve the safety of immune cell therapies.
• When using immune cells to treat disease, there is a risk that the cells switch from protective to destructive behaviour.
• Studies in mice have allowed researchers to identify the cells most at risk of becoming harmful.

By purifying cells using markers of instability, or following a two-step purification process, the researchers are able to produce a robust set of protective cells. Research in mice, published today by researchers at the Babraham Institute, UK and VIB-KU Leuven, Belgium, provides two solutions with potential to overcome a key clinical limitation of immune cell therapies. Cell therapy is based on purifying cells from a patient, growing them up in cell culture to improve their properties, and then reinfusing them into the patient. Professor Adrian Liston, Immunology group leader at the Babraham Institute, explained: “The leading use of cell therapy is to improve T cells so that they can attack and kill a patient’s cancer, however the incredible versatility of the immune system means that, in principle, we could treat almost any immune disorder with the right cell type. Regulatory T cells are particularly promising, with their ability to shut down autoimmune disease, inflammatory disease and transplantation rejection. A key limitation in their clinical use, however, comes from the instability of regulatory T cells – we just can’t use them in cell therapy until we make ensure that they stay protective”. By identifying the unstable regulatory T cells, and understanding how they can be purged from a cell population, the authors highlight a path forward for regulatory T cell transfer therapy. The study is published today in Science Immunology.

T cells come in a large variety of types, each with unique functions in our immune system. “While most T cells are inflammatory, ready to attack pathogens or infected cells, regulatory T cells are potent anti-inflammatory mediators”, Professor Susan Schlenner, University of Leuven, explains. “Unfortunately this cell type is not entirely stable, and sometimes regulatory T cells convert into inflammatory cells, called effector T cells. Crucially, the converted cells inherit both inflammatory behaviour and the ability to identify our own cells, and so pose a significant risk of damage to the system they are meant to protect.”

The first key finding of this research shows that once regulatory T cells switch to becoming inflammatory, they are resistant to returning to their useful former state. Therefore, scientists need to find a way to remove the risky cells from any therapeutic cell populations, leaving behind the stable regulatory T cells. By comparing stable and unstable cells the researchers identified molecular markers that indicate which cells are at risk of switching from regulatory to inflammatory. These markers can be used to purify cell populations before they are used as a treatment.

In addition to this method of cell purification, the researchers found that exposing regulatory T cells to a destabilising environment purges the unstable cells from the mixture. Under these conditions, the unstable cells are triggered to convert into inflammatory cells, allowing the researchers to purify the stable cells that are left. “The work needs to be translated into human cell therapies, but it suggests that we might be best off treating the cells mean”, says Professor Adrian Liston. “Currently, cell culture conditions for cell therapy aim to keep all the cells in optimal conditions, which may actually be masking the unstable cells. By treating the cultures rougher, we may be able to identify and eliminate the unstable cells and create a safer mix of cells for therapeutic transfer”. Dr Steffie Junius, lead author on the paper, commented: “The next stage in the research is to take the lessons learned in mice and translate them into optimal protocols for patients. I hope that our research contributes to the improved design and allows the development of effective regulatory T cell therapy."

Establishing a thorough process to improve cell population stability in mice helps to lay the groundwork for improved immune cell therapies in humans, although the methods described in this work would require validation in humans before they were used in cell therapy trials. Tim Newton, CEO of Reflection Therapeutics, a Babraham Research Campus-based company designing cell therapies against neuro-inflammation and independent from the research, commented on the translational potential of the study: "This research makes a significant impact on regulatory T cell therapeutic development by characterising unstable subsets of regulatory T cells that are likely to lose their desirable therapeutic qualities and become pro-inflammatory. The successful identification of these cells is of great importance when designing manufacturing strategies required to turn potential T cell therapeutics into practical treatments for patients of a wide range of inflammatory disorders."

Read the full paper here.

Go with the flow – a new algorithm streamlines and improves flow cytometry analysis

Key points:

• A new algorithm developed by researchers at the Babraham Institute provides a fast and effective way to reduce errors in flow cytometry data analysis, overcoming a major restriction on harnessing the full potential of the power of flow cytometry in cell analysis.
• The tool, called AutoSpill, addresses the problem of overlapping signals and autofluoresence, which can be misinterpreted as genuine results.
• Researchers can use the tool, available online and through the software package FlowJo, to easily reduce compensation errors in their flow cytometry data.

Flow cytometry is a key investigative tool used in biomedical research, allowing researchers to identify, separate and study cells according to their characteristics, often working with cell samples containing millions of cells at an analysis pace of a million cells per minute. Cell identification is achieved by labelling cells with fluorescent tags. As with personal gadgets and devices, innovation in molecular biology technologies isn’t standing still. Advances in flow cytometry have allowed scientists to gather data on a growing number of parameters, simultaneously detecting over 30 different tags at a time to allow more sophisticated analyses and much deeper levels of insight. However, while flow cytometry equipment has been updated, the accompanying computational requirements have received less attention, until now. AutoSpill, an algorithm developed by researchers at the Babraham Institute and the VIB Center for Brain Research, brings data processing in line with state-of-the-art machines, simplifying data analysis and increasing accuracy. The new technique is published in Nature Communications today.

Immunology programme senior group leader Prof. Adrian Liston, explained: "Flow cytometry is a foundational technology across many different biomedical research areas, and is a key diagnostic tool in immunology, haematology and oncology. Despite the technical progress over the past decades, the technology has been held back by the mathematical processing of the data. Our new approach reduces error by 100,000-fold, making research and diagnostics more accurate. The collaboration with FlowJo has enabled us to instantly reach 80,000 users. It is very gratifying to see computational biology have a direct and real impact on research and diagnostics."

Using multiple fluorescent signals raises a key issue in flow cytometry called spillover. Spillover occurs because each tag, called a fluorophore, emits light within a range of wavelengths, giving it a unique colour. When multiple fluorophores are used, the signals begin to overlap. To accurately distinguish between two distinct fluorophore signals, researchers must process their data to compensate. Because flow cytometry uses so many different colour tags on each cell, the spillover between colours quickly accumulates, limiting scientists’ power to draw reliable conclusions from their results. The processing of data to remove the spillover between the different colours, known as compensation, is necessary for all flow cytometry experiments. Current methods require many hours of manual work, but AutoSpill reduces the process to minutes.

Dr Rachael Walker, Head of the Institute Flow Cytometry facility, commented: “The new AutoSpill Fluorescence Compensation algorithm is a great tool for quick, simple and accurate compensation. It allows compensation to be accurately calculated on samples where the traditional algorithm is difficult to use. AutoSpill’s integration into the FlowJo post-acquisition software highlights the importance of this new compensation method.”

Another limitation of flow cytometry is autofluoresence, fluorescence produced naturally by cells. The removal of these artefacts by AutoSpill is particularly useful for cancer biologists as tumour cells are high in autofluorescence, which can confuse identification of the type of tumour cell present. By solving these sources of error, AutoSpill can help remove false positives from cell analyses, ensuring more accurate data interpretations.

AutoSpill is available through open source code and a freely-available web service. AutoSpill, and a complementary related tool, AutoSpread, are also available in FlowJo v.10.7. Dr John Quinn, Director of Science and Product Development, FlowJo added: “AutoSpill & AutoSpread have been a revelation for FlowJo users. Compensation has long been one of the most perplexing aspects of cytometry, with the most critical requirement being pristine compensation controls collected for each and every parameter in an experiment. Overall, the combination of these two tools makes compensation both easier and more robust. As an indicator of the popularity of this new approach, the webinar held in conjunction with Nature to introduce AutoSpill / AutoSpread in FlowJo has been viewed over 400 times after the initial live event. We at FlowJo believe the AutoSpill / AutoSpread approach will be the primary means of approaching compensation moving forward.”

Battle Robots of the Blood reading

Me and Hayden read "Battle Robots of the Blood" together.

European “ImmunAID” project for the diagnosis of rare autoinflammatory systemic diseases launched in Belgium

The project wishes to diagnose rare autoinflammatory systemic diseases through the identification of biomarkers

In December 2020 a new project has been launched in the University Hospitals Leuven. The ImmunAID project aims to identify new tools for the diagnosis of systemic auto-inflammatory diseases (SAID). SAID are a complex and evolving group of rare diseases characterised by extensive clinical and biological inflammation. These conditions are caused by a dysregulation of the innate immune system leading to a release of immune cells and mediators provoking fevers, tissue and organ inflammation and damage.

Sometimes it is difficult for the physicians to make a correct diagnosis, since the main symptoms of these diseases (such as fever, rash, joint pain, etc.) are also present in many other conditions. Thus, a patient may have received on average up to 5 inappropriate or ineffective treatments before being properly diagnosed, having a great impact on their health and quality of life. The aim of ImmunAid is to understand the mechanisms that drive the pathology in order to provide better diagnosis and care for patients with these rare but potentially devastating diseases.

An unprecedented body of clinical and biological data in the field of SAID

This new project aims to find new and more effective ways to diagnose SAID. While it is already known that some SAID are due to specific genetic mutations, a large number of SAID can only be detected by a set of clinical signs and symptoms and after other diagnostic possibilities have been excluded. Since SAID are rare conditions, a large group of patients suffering from various SAID is being recruited throughout Europe. As such, the ImmunAID cohort represents a very important tool for researchers defining biological fingerprints, or biomarkers, specific to distinct SAID.

The team expects to find a set of biological features common to all SAID, which will allow to quickly confirm or refute the diagnosis of suspected autoinflammatory syndrome. In addition, for each SAID, a list of characteristic biomarkers and an algorithm will be generated to allow the physician to make an appropriate diagnostic assessment.

In order to achieve the project's objectives, biological samples collected from the patients will be analysed in a European-wide research network by set of state-of-the-art technologies and will generate an unprecedented amount of data (genomics, transcriptomics, proteomics and microbiome). Simultaneously, other analyses will focus on immune cells, molecular mechanisms and specific agents of the immune system (cytokines, etc.). All data generated will be subjected to artificial intelligence and modelling analysis.

Prof. Carine Wouters, paediatric rheumatologist at the University Hospitals Leuven, is highly committed to the success of the project "We are delighted and proud to be able to work with ImmunAID partners as it represents a unique opportunity for the European scientific community to advance research in an important field of rare diseases that can only be tackled at large scale. We will do our best to come up with meaningful results that will improve patients’ diagnosis and medical care.”

Leuven teams are the forefront of the project

The teams of the Leuven University Projects are at the forefront of the project. The activities carried out in the Belgian centre will be two-fold. First, the team from professor Carine Wouters and professor Steven Vanderschueren will be in charge of recruiting patients suffering from monogenic SAID (FMF, CAPS, TRAPS, MKD) or genetically-undiagnosed SAID (Still disease, neutrophilic dermatosis, Schnitzler syndrome, Takayasu arteritis, Kawasaki disease, Behçet disease, chronic osteitis, recurrent pericarditis and chronic systemic inflammation of unknown origin).

Second, professor Wouters, professor Patrick Matthys and professor Paul Proost from the Rega Institute and KU Leuven department for Microbiology, Immunology and Transplantation will be involved in the biochemical and biological analysis of the samples. The team of Carine Wouters and Patrick Matthys will apply their extensive knowledge on Natural Killer cells to identify and characterize their possible altered activity in SAID patients. On the other hand, the team of Paul Proost will study whether modifications of messengers of the immune system (cytokines and chemokines) in patients play a role in regulation of the inflammation processes. The team of professor Stephanie Humblet-Baron and professor Adrian Liston will analyse in-depth the immune cellular compartment of the blood of affected patients in addition to genetic investigation in order to identify new genes responsible for SAID.

These activities are intended to gain insight into the mechanisms triggering the aberrant behaviour of the autoinflammation process. The results will be pooled with other analyses from other European research laboratories to help identify biomarkers of the diseases and possible therapeutic interventions.   

Regarding the ImmunAID project: ImmunAID is a research project (www.immunaid.eu), which aims to identify a set of disease-specific biomarkers to confirm the diagnosis of SAID. ImmunAID is implemented by a large consortium (25 partners in 12 European countries) and has been funded with € 15.8 million by the European Commission. The ImmunAID project has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 779295.

IL-2 cytokine networks

If anyone is interested in our lab's work on IL-2 cytokine networks, I just gave a seminar on the topic, which I am putting up here:

It is a new talk for me, and was an interesting one to write. I started to work on IL-2 right at the start of my PhD. I was very keen to return to the topic when I opened my own lab in Belgium (2009), with one of my first PhD students (Dr Wim Pierson) working on the niche-sensing and niche-filling negative feedback loop that provides a stable number of Tregs in the system. (An excellent collaboration with one of my favourite immunologists, Prof Daniel Gray from WEHI, Australia).

Then Prof Stephanie Humblet-Baron joined my lab for a post-doc, wanting to work on a disease known as Familial hemophagocytic lymphohistiocytosis (FHL). At the time, this was thought to be a disease of CD8 hyper-activation and IFN-gamma. Thanks to great work by Stephanie, in mouse and human, we now know that FHL is only partly driven by IFN-gamma, and instead a key part of pathogenesis comes from flipping the negative feedback loop between IL-2 and Tregs into a postivie feedback loop between IL-2 and CD8 T cells.

Right back in 2009 we started to work on a new genetic switch that would let us turn IL-2 on in different cell types. At first I just wanted to see what would happen if Tregs could make their own IL-2. By breaking that dependency on exogenous IL-2 do you get a run-away Treg reaction? (answer: yes, yes you do). Once we finally made the mice, however, it just opened so many different doors. What happens if CD8 T cells make their own IL-2? How about NK cells, dendritic cells, B cells? What if we turn it on in different organs? It has really been a phenomenal mouse that just kept on delivering interesting results. Dr James Dooley led a team working on the mouse, and more recently Dr Carly Whyte drove the project to publication. Or, at least, pre-publication - you can see the paper here on BioRxiv. So many interesting aspects of IL-2 biology were illuminated by this work - easiest to show in a circuit diagram:

I hope you enjoy the seminar. Keep an ear out for the muffled bang at the 29 minute mark. It doesn't sound like much on the audio feed, but across Cambridge we all jumped up as the windows rattled and the building shuddered. I fumbled the graph on this slide, calling Tregs Tconv by mistake, wondering if an explosion had gone off downstairs. Fortunately it was just a sonic boom as fighter jets scrambled overhead.

Top 10 health innovations of 2020

Great to see our recent Cell paper on brain T cells licensing microglia listed as one of the top 10 health innovations of 2020!