Interview with iiSIAR podcast

Nobel Prize for regulatory T cells

A small primer on the Nobel Prize awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi today. This prize was for combining two separate fields of immunology research - genetic research on IPEX and immunology research of regulatory T cells (Tregs), with enormous impact on biology/medicine.

First, let's talk about IPEX. It is short for "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome", which is a bit of a mouth-full. Essentially, it is a severe autoimmune disease, impacting boys (inherited only from the mother), which is fatal in early childhood unless treated. By coincidence, there was a mouse strain with the same disease and inheritance pattern called “Scurfy”, allowing it to be studied in mice.

IPEX/Scurfy was rather mysterious, but because of the inheritance pattern it was quickly mapped to the X chromosome. Several teams of scientists worked on mapping this disorder down to the gene level, with Brunkow and Ramsdell leading the teams that identified FOXP3 as the causative gene in both humans and mice, with major papers in 2001.

Completely independent of this, we had the field of regulatory T cells. There were some misleading experiments on "suppressive T cells" early on, a field which rapidly built and then collapsed in the 80s. Few of those experiments had lasting impact in the field of immunology, but an exception were the papers of Nicole Le Douarin in 1987/1988. She grafted the wing buds of quail onto embryonic chickens, which developed into chickens with quail wings, which were then rapidly rejected by the immune system. The key finding, however, was that if the proto-thymus was also transplanted the chickens kept their wings long term. Here it was quite important that the chicken was used, as it has 10-16 anatomically-separated thymic lobes and you only need to transplant one to get transplant acceptance. This means that the chicken developed a form of tolerance mediated by T cells educated in the thymus but effective in the periphery.

It was a hard and unpopular field for decades, however, with the key pioneers being Fiona Powrie and Shimon Sakaguchi. They chased up independent sets of T cells with immunosuppressive properties, using different markers on what were ultimately the same cells – regulatory T cells, potent at shutting down immune responses in multiple different assays.

It wasn’t until 2003 that regulatory T cells gained wide uptake by the immunology community. This key breakthrough happened by the linking of FOXP3, the IPEX/Scurfy gene, and regulatory T cells. Three groups, lead by Sakaguchi, Ramsdell and Sasha Rudensky, all demonstrated that FOXP3 was acting as the master transcription factor that converted regular T cells into the immunosuppressive regulatory T cells. Suddenly everyone could study Tregs and manipulate their genetics, with tool after tool coming online (such as Foxp3GFP, Foxp3Cre, Foxp3DTR – Rudensky, Tim Spawasser and Jeff Bluestone, among others). It triggered an exponential increase in papers on regulatory T cells, linking them to disease after disease.

The impact has been enormous, with regulatory T cells going from being a niche frowned-upon subset of immunology, to underpinning our entire understanding of how the immune system works. This is obvious important for diseases where we want to shut down the immune system, such as autoimmunity, allergy, transplantation and inflammatory diseases. There anything to boost the number or function of regulatory T cells could be clinically beneficial, with the therapeutic interleukin 2 (IL2) being the prototype therapy and still in clinical use today. It was also a key discovery for contexts where we want to activate the immune system, in particular in cancers, which locally recruit regulatory T cells to protect themselves from immune clearance. Treatments such as anti-CTLA4 essentially allow inflammatory T cells to bypass suppression by regulatory T cells, and have transformed the oncology space. The pre-clinical pipeline is even richer, so we can expect many more regulatory T cell-based therapies to enter the market soon!

Huge congratulations not only to the team leaders who won this prize, but all the students, technicians and expert scientists who did the work that underpins this discovery. Their work, and the work of those following in their footsteps, is changing the future for patients!

Also see a few articles where I was quoted in the Guardian and Science.

ImmunoTea interview

I'm interviewed in the latest episode of ImmunoTea. Take a listen for all things Tregs and neuroimmunology!

Understanding tissue migration

We have an exciting new bioRxiv story that just went live! This one takes a computational immunology approach to understanding tissue-resident lymphocytes. The story highlights the extra value mathematical modelling can bring to biology.

It starts with a large multi-tissue multi-timepoint parabiosis experiment we ran to understand tissue Tregs. Václav Gergelits, lead author on the study, saw greater potential in this dataset to understand the kinetics of lymphocyte migration broadly.

We extracted turnover data for CD4, CD8, Treg, B cells and NK cells from 17 tissue sources, and generated a sophisticated model of migration, activation and death for each lineage and tissue. The Markov chain modelling found high-confidence solutions that matched the empirical data beautifully.

This tells us a probabilistic model and three distinct states (resting/activated/resident) are sufficient to recapitulate the complex migratory and tissue-residency behaviour of these cells. The cell states change probabilities, but the behaviour is still *probabilistic*.

This means lymphocytes do not have a residency "clock". We can measure the average dwell times for resident cells, but if this average residency time is 3 weeks, it does not mean cells have a 3-week timer. It means the cells have a daily probability of leaving that gives a 3 week average. The dice roll comes up earlier for some cells than for others, within those cells being intrinsically different. Like radioactive decay of atoms, it is just probability - there is nothing intrinsically different about the uranium atoms that decay after a week vs those that decay after a million years, they just had different rolls of the dice.

This approach can explain much of the variation in cell fate without needing to invoke cellular heterogeneity! Two identical cells can have highly divergent outcomes simply because of probability, without different underlying biology. In fact, we can create thousands of identical "digital cells", model them with these simple rules, and we get the empirically-observed range of dwell-times. There is no need to invoke TCR clonality or the like - it is simply an emergent property of cells with probabilistic kinetics!

A great example of applied mathematics informing biology!

Take a read of the pre-print here.

Understanding vaccination in transplant patients

We have a new systems vaccinology paper out at npj Vaccines!

The study tackles the problematic question of why transplant patients responded so poorly to the COVID vaccine. While most people had great antibodies from a single dose, only half of transplant patients have responded even after three!

We took blood from 20 healthy, 31 lung transplant and 59 kidney transplant patients prior to vaccination, and profiled 444 immunological parameters, to get a comprehensive systems immunology profile. We then followed who did and didn't respond to the vaccine, to find the immunological associates.

First up, there are clinical effects: Vaccine response was especially poor soon after transplantation, and in patients on immunosuppressive cocktails, especially those including MMF. Even taking this into account, there were immunological drivers associated with poor response.

As you might predict, the patients that responded best were those with an immune profile that had returned closer to normal post-transplantation. In fact, you could predict vaccine response with 93% accuracy just based on 10 immune parameters.

 

Oddly though, some patients were able to hobble together a poor but detectable response after two shots. These patients didn't have a more normal immune profile, and had quite unusual relationships between immune populations, suggesting that they had put together a poor-but-functional "kludge".

This study was a joint initiative from our lab, Arnaud Marchant's lab at at ULB and Stephanie Humblet-Baron's lab at KU Leuven. 

Huge thanks to all team members, especially Nicolas Gemander, Julika Neumann, Rafael Veiga and Isabelle Etienne for their leadership roles.

Biggest thanks of all to the patients who volunteered for the study!

Read the full paper here

Creating settings on the Aurora

From the talented Oliver Burton:

Tissue Tregs seminar

Recording of a seminar I gave for the Cytek seminar series, on tissue-resident regulatory T cells.

Designer IL2 mutations for clinical use

We have a new pre-print out, on novel designer IL2 mutations!

IL2 is a powerful immunomodulator, but the dual roles make it complex to use, and many designer mutations reduce bioactivity or result in poor production. This makes it much harder to move these muteins to the clinic.

Rob van der Kant, Joost Schymkowitz and Frederic Rousseau from the VIB Switch lab took up the challenge of designing new IL2 mutants that not only improve the specificity for Tregs or CD8 T cells, but also maintain bioactivity and actually improve production capacity. They sent the designs over to us to test!

Great work from Amy Dashwood screened these mutations designs in vitro, with in vivo testing by Ntombizodwa Makuyana resulting in a set of mouse and human IL2 muteins with the desired biological properties. In particular we solve some of the common issues with IL2 muteins by considering the bound and unbound structures. For example, to make IL2 specific for Tregs, the approach is to allow binding to IL2RA, the high affinity receptor sub-unit used by Tregs, while block binding to the IL2RB used by CD8 T cells. The problem is that Tregs also need the full IL2RA-IL2RB-IL2RG trimer to assemble for optimal signal. So the typical Treg mutein is more specific, but also has poorer bioactivity. We solved this by creating a block between IL2 and IL2RB that moves out of the way after IL2 binds IL2RA, allowing the full trimer to form. These muteins are not only superior to the original IL2 in terms of cellular specificity, but by removing the aggregation-prone regions. By identifiying the aggregation gateway residues and changing them to be aggregation-resistant, we can further improve these muteins by making them aggregation resistance. The net effect is that the IL2 muteins we made are more specific for either Tregs or CD8 T cells, and will also be cheaper and easier to produce - the perfect combo for biologic drugs!

Our take-home message: if you are engineering proteins for therapeutic use, remember to take into account production, aggregation and bioactivity. These factors count when it comes to making a drug!

Take a look at the full paper on BioRxiv.

Discovery of ‘new rules of the immune system’ could improve treatment of inflammatory diseases, say scientists.

Scientists at the University of Cambridge have discovered that a type of white blood cell - called a regulatory T cell - exists as a single large population of cells that constantly move throughout the body looking for, and repairing, damaged tissue.

This overturns the traditional thinking that regulatory T cells exist as multiple specialist populations that are restricted to specific parts of the body. The finding has implications for the treatment of many different diseases – because almost all diseases and injuries trigger the body’s immune system.

Current anti-inflammatory drugs treat the whole body, rather than just the part needing treatment. The researchers say their findings mean it could be possible to shut down the body’s immune response and repair damage in any specific part of the body, without affecting the rest of it. This means that higher, more targeted doses of drugs could be used to treat disease – potentially with rapid results.

It's difficult to think of a disease, injury or infection that doesn’t involve some kind of immune response, and our finding really changes the way we could control this response.

Adrian Liston

“We’ve uncovered new rules of the immune system. This ‘unified healer army’ can do everything - repair injured muscle, make your fat cells respond better to insulin, regrow hair follicles.  To think that we could use it in such an enormous range of diseases is fantastic: it’s got the potential to be used for almost everything,” said Professor Adrian Liston in the University of Cambridge’s Department of Pathology, senior author of the paper.

To reach this discovery, the researchers analysed the regulatory T cells present in 48 different tissues in the bodies of mice. This revealed that the cells are not specialised or static, but move through the body to where they’re needed. The results are published today in the journal Immunity.

“It's difficult to think of a disease, injury or infection that doesn’t involve some kind of immune response, and our finding really changes the way we could control this response,” said Liston.

He added: “Now that we know these regulatory T cells are present everywhere in the body, in principle we can start to make immune suppression and tissue regeneration treatments that are targeted against a single organ – a vast improvement on current treatments that are like hitting the body with a sledgehammer.”

Using a drug they have already designed, the researchers have shown - in mice - that it’s possible to attract regulatory T cells to a specific part of the body, increase their number, and activate them to turn off the immune response and promote healing in just one organ or tissue.

“By boosting the number of regulatory T cells in targeted areas of the body, we can help the body do a better job of repairing itself, or managing immune responses,” said Liston.

He added: “There are so many different diseases where we’d like to shut down an immune response and start a repair response, for example autoimmune diseases like multiple sclerosis, and even many infectious diseases.”

Most symptoms of infections such as COVID are not from the virus itself, but from the body’s immune system attacking the virus. Once the virus is past its peak, regulatory T cells should switch off the body’s immune response, but in some people the process isn’t very efficient and can result in ongoing problems. The new finding means it could be possible to use a drug to shut down the immune response in the patient’s lungs, while letting the immune system in the rest of the body continue to function normally.

In another example, people who receive organ transplants must take immuno-suppressant drugs for the rest of their lives to prevent organ rejection, because the body mounts a severe immune response against the transplanted organ. But this makes them highly vulnerable to infections. The new finding helps the design of new drugs to shut down the body’s immune response against only the transplanted organ but keep the rest of the body working normally, enabling the patient to lead a normal life.

Most white blood cells attack infections in the body by triggering an immune response. In contrast, regulatory T cells act like a ‘unified healer army’ whose purpose is to shut down this immune response once it has done its job - and repair the tissue damage caused by it.

The researchers are now fundraising to set up a spin-out company, with the aim of running clinical trials to test their findings in humans within the next few years.

The research was funded by the European Research Council (ERC), Wellcome, and the Biotechnology and Biological Sciences Research Council (BBSRC).

Reference: Liston, A. ‘The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program.’ Immunity, June 2024. DOI: 10.1016/j.immuni.2024.05.023

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In brief

• A single large population of healer cells, called regulatory T cells, is whizzing around our body - not multiple specialist populations restricted to specific parts of the body as previously thought.
• These cells shut down inflammation and repair the collateral damage to cells caused after our immune system has responded to injury or illness.
• Tests, in mice, of a drug developed by the researchers showed that regulatory T cells can be attracted to specific body parts, boosted in number, and activated to suppress immune response and rebuild tissue.
• Current anti-inflammatory drugs used for this purpose suppress the body’s whole immune system, making patients more vulnerable to infection.
• The discovery could lead to more targeted treatments, with fewer side-effects, for issues from lengthy COVID infections to autoimmune diseases like multiple sclerosis. Clinical trials in humans are now planned.

After the Smoke Clears: Scars on the Immune System

Check out this article written in The Scientist by Danielle Gerhard, on the epigenetic marks of smoking on the immune system. A few quote from me in the piece:

“There is no human immune system; there is everyone's individual immune system,” said Adrian Liston, an immunologist at the University of Cambridge who was not involved in the study. “We really need to study things at the scale that the group in Paris is studying if we want to understand what's going to be relevant to human health at a population level.”