Liston-Dooley lab at the Cambridge Festival!

Our lab is gearing up for the Cambridge Festival! A lot of amazing activities, with something for everyone, so hopefully everyone in Cambridge can come and join at least one of these.

First of all, for our youngest visitors come along to a book reading of our kids books "Maya's Marvellous Medicine" and "Battle Robots of the Blood". We'll have some colouring in too, to keep them busy.

For kids a little older, Family Day at Pathology has a ton of activities! Our lab is hosting a display of "VirusFighter". See how your kids would have done as PM during the pandemic, or test whether they can successfully engineer a bioweapon to stop an invasion of wombats! (They can also play online now!)

 For all ages, we have a real treat, Sensory Science. This is a fantastic program that uses multi-sensory art to communicate the science of pathology. Honestly, everyone should come and experience this exhibit at St Catharine's College, the teams have put in so much work into their art piece. Our lab has coordinate the program and is exhibiting new art on neuroinflammation and cancer formation. We are also hosting the amazing Dr Erica Tandori, who started the Sensory Science movement back in Australia, and specialises in making science communication accessible to the blind and low vision community.

Finally, adults interested in the immune system are welcome to join my public seminar on how diversity shapes our immune responses!

Congratulations to Jasmine Hughes!

Congratulations to Jasmine Hughes for her Cook Society Award for dedicating herself to social justice, equality and strengthening the campus community, during her time at Duke University! I'm glad to say she is keeping up the focus during her PhD here at the University of Cambridge!

New positions in the lab!

We are recruiting two new positions, a Postdoctoral Research Scientist and a Research Laboratory Technician, to join our lab! 

This translational research project aims to develop novel technologies for treating neuroimmunology into clinic-ready molecules. You will contribute to the optimisation of therapeutics for brain delivery to patients, as part of the commercialisation pathway for a recently developed neuroinflammation treatment (Yshii et al, Nature Immunology 2022). The laboratory is an inclusive, international and diverse team, supportive of your personal and career development. A positive approach to kind and collaborative interactions with the team is essential! You will benefit from the collaborative and collegial environment of the laboratory, and potential career growth opportunities within the laboratory and within the developing spin-off company Aila Biotech are possible for a successful post-holders. 

The Post-doctoral Scientist post would be suitable for a new PhD graduate who is motivated to develop new skills in both neuroimmunology and in commercialisation. The post is designed to result in scientific publications and patent applications. Post-doctoral Scientist's apply here.

The Research Laboratory Technician post would be suitable for a candidates from a range of backgrounds, such as experience in animal handling, or a basic laboratory experience, or a Masters-level degree in immunology, neuroscience, or a related field. Applicants are not expected to enter with the full range of these skills or experiences. Research Laboratory Technician's apply here.

Congratulations Dr Julika Neumann!

Congratulations to the amazing Dr Julika Neumann, who just graduated from the lab, as our final Belgian PhD!

Julika secretly did two PhDs rather than one, with an outstanding clinical immunology PhD where she discovered a new immunodeficiency (and won the Golden Pipette!) and another systems immunology project on SARS-CoV2, with the first paper published and several systems vaccinology papers coming out soon!

Julika was a talented immunologist and bioinformatician, but above all an exceptional team-player and detail-orientated fixer. We all congratulate Julika on an exceptional PhD and her positive impact on all of those around her over the past four years. All the best Julika!

2023 lab retreat re-cap

We just completed a very successful lab retreat, this year held at St Catharine's College, Cambridge. It was perfect timing, with our new students starting and getting to meet the entire team, not to mention getting incredible feedback from everyone on their new projects. I'm so proud to be a part of such an amazing team of scientists!

I started by recapping the successes of the lab in 2023 - and there have been plenty! 16 papers published so far this year (and another 12 submitted!), ~£1.5m brought into the department in grants and fellowships, our spin-off company Aila Biotech getting into an accelerator program, and successful alumni moving on to great things! But we run the lab retreat for the future, not the past. Two full days of exciting science, from projects right at the conceptual phase through to projects that have matured and need the finishing touches. Of course it wouldn't be a lab retreat with the presentation of the Golden Pipette! This year's went to Amy Dashwood, a talented scientist and a positive influence on team culture. 

We had great team building exercises too! We had to guess each person's pathway to becoming a scientist, picking out baby photos and origin story, matching up role-models to teenage pictures, and picking out the motivation for each lab member to be in science today. Plus a set of AI-generated limericks for each person, and social activities from a pub lunch to walks through the Cambridge botanic gardens and museums. 

I also really appreciated having our external guests come in to give their wisdom to the team, and it was especially nice that many of our external experts are lab alumni!

Overturning how we think about immune regulation across the body

by Kat Steer

A Fellow at St Catharine’s College has led extensive new research that looks set to overturn the established model about how one type of white blood cell regulates immune responses in tissues – what was assumed to be a static part of the immune system is actually dynamic, opening the door to new treatments for a range of conditions.

Professor Adrian Liston (2023) is Professor of Pathology at the University of Cambridge and has run a research laboratory with Dr James Dooley since 2009, which relocated to Cambridge’s Department of Pathology earlier this year.

Professor Liston explains, “All of us are familiar with immune activation in our daily lives – the body’s response to injury or infection – but immune regulation is just as important to our health. A poorly regulated or hyperactive immune system can be hugely damaging, as we see in cases of flu, COVID-19, autoimmune diseases and inflammatory diseases. The team based at our laboratory have been conducting a broad range of research to learn more about the different processes and cells that are key to immune system regulation.”

Their latest findings are focused on a group of white blood cells known as regulatory T cells (Tregs) which have a role in regulating or suppressing other cells in the immune system. Over the last 10 years, scientists have established that Tregs are found not just in our blood but also throughout different tissues in the body. It is also known that Tregs play a significant role beyond controlling the immune system by enabling the body to return normal (homeostasis) and orchestrating repair and rejuvenation after an immune response.

“A decade of research has begun to establish the importance of Tregs but there is still so much we don’t know for sure. Like so many other scientists, we accepted the prevailing wisdom that Tregs travel into tissues where they remained as a static part of the immune system and specialised to their surroundings – an idea borrowed from evidence about another type of white blood cell (macrophages). We never set out to challenge this model, but our new findings indicate that these Tregs are really different from what we all thought.”

After an earlier successful study into Treg cells in the brain, the Liston-Dooley laboratory set out to complete an ambitious systematic analysis of the Tregs throughout the body, which has involved studying tissues from 48 different tissues in mice.

“It was only once we took global look at the body as a whole that it was possible to see for the first time that the Tregs in tissues are not specialised or static. In fact, they are highly dynamic and percolate throughout the body to serve different organs, moving from one place to the next as needed.

“It is exciting to know more about these important cells and potentially open up a new avenue for treating diseases – if we can find a way of boosting the number of Tregs in targeted areas of the body, then we can help the body do a better job of repairing itself or managing immune responses. We are in the early stages of planning a clinical trial to understand more about the benefits of boosting the levels of Tregs and look forward to sharing what we find.”

This work was supported by the European Research Council, the Wellcome Trust, and the Biotechnology and Biological Sciences Research Council.

Pre-print details

Burton O, et al. The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program. bioRxiv 2023.08.14.553196; doi: https://doi.org/10.1101/2023.08.14.553196

Golden Pipette awarded to Amy Dashwood

Congratulations go to Amy Dashwood, winner of the 2023 Golden Pipette! The Golden Pipette is handed down from winner to winner in recognition of elegant experiments and a positive contribution to lab culture. This year Amy has won the Golden Pipette for her elegant experiments creating a genetic chimera system to analyse microglia homeostasis, and for being an outstanding lab citizen and mentor to undergraduate students. Well done Amy!

Congratulations Amy Dashwood!

Best Student Talk at the Babraham Institute Lab Talks. Well deserved!

Stay tuned to find out her really cool work on microglia homeostasis!

The Tissue Treg project

Biggest paper yet from the lab now a preprint on BioRxiv. A massive open science resource on tissue Tregs, and what makes Tregs tick in the tissues.

This project started back when we thought that tissue Tregs formed by seeding tissues and differentiating into unique terminal cells. We had examples of fat Tregs and muscle Tregs becoming unique permanent residents, and wanted to look at Tregs across the tissues.

We undertook a massive project to look at Tregs across 48 different tissues. At first glance, tissue Tregs looked special. Take a tissue and compare it against lymphoid/blood Tregs and the differences are huge. But the more tissues you add, the more they look the same. The only three distinct phenotypes were gut, lymphoid and bulk non-lymphoid. (Try our interactive web-browser resource). They have the same phenotypes, they use the same genetic triggers to differentiate and they only stay in the tissues for around 3 weeks. In short, the "seeding & specialisation" model doesn't fit the data.

Instead we came up with the "pan tissue" model, where tissue Tregs slowly percolate between different tissues. We've spent years testing this model in every possible way. We used the TCR as genetic barcodes, showing that the same Treg #clones are found in different tissues. We used ProCode technology to make #retrogenics for the tissue Treg TCRs, formally demonstrating that they impart a multi-tissue Treg fate. We extracted cells from tissues and reintroduced them, showing that they are tissue-agnostic on rehoming. By every test, the "pan-tissue" model holds strong.

What is amazing is that tissue Tregs have so many key functions in tissue repair and homeostasis, and now we find that it is the same cells that are able to restore the balance across all of these different tissues. Tissue Tregs are global homeostatic police. They are regulatory cells with a pan-tissue beat. A truly amazing cell type.

Could only have happened due to an amazing team - lead by Oliver, Burton, Orian Bricard and James Dooley. 

A New Hope for IPEX patients

A new paper from our lab suggests a novel approach to treating IPEX patients. IPEX is a rare severe primary immunodeficiency, caused by a genetic deficiency in the gene FOXP3, which results in a lack of anti-inflammatory regulatory T cells.

IPEX is usually fatal in childhood if left untreated. The only cure is a haematopoietic stem cell transplantation, however patients are often so sick from autoimmunity that they are in poor condition to receive a transplant. The patients are put on symptomatic support (hormonal and nutritional supplements to compensate for the damaged organs) and immunosuppressive drugs to reduce further damage. These immunosuppressive drugs are typically combinations of cyclosporine A, tacrolimus, rapamycin and corticosteroids, although recently biologics such as orthoclone have been suggested. Unfortunately the patient cohort has been too small and heterogeneous to allow a proper clinical trials as to which immunosuppression regimen works best. 

We sought to answer this by turning to the mouse model - also with a genetic deficiency in Foxp3 and a lack of regulatory T cells. We developed a comprehensive pathology scoring system for the model that takes into account the multiple different autoimmune symptoms, and then tested in a side-by-side comparison rapamycin (the most common standard treatment), anti-CD4 antibody (analgous to orthoclone in its proposed approach) and CTLA4-Ig (based on our prior work on CTLA4-Ig compensating well for Treg-deficiency). 

The results were striking. As seen in patients, rapamcyin cleared up some of the skin pathology, but otherwise it had little impact on the course of pathology in the mice. Anti-CD4 antibody prevented many of the immunology symptoms, but again, didn't actually improve the aggregate health outcomes of the mice. CTLA4-Ig, by contrast, improved essentially every parameter - the mice started gaining weight like normal, improved their serology, skin pathology and organ histology - and had greatly improved life-spans. Most importantly, the overall condition of the CTLA4-Ig-treated mice improved to such an extent that they were capable of supporting curative bone-marrow transplants: survival improved from 50% to 100% in mice given CTLA4-Ig prior to transplantation. 

There are caveats to every disease model, however we believe this is sufficient evidence to strongly consider a clinical trial of CTLA4-Ig (abatacept) in IPEX patients. The genetic and cellular defects are entirely conserved between mouse and human in this case, and the drug is in widespread use in patients for other autoimmune conditions (such as arthritis). We know that there are IPEX patients who respond poorly to the current standard treatments and need to improve their condition before receiving a bone-marrow transplant. CTLA4-Ig treatment could be the bridge that these patients need to the curative transplantation!

Thanks to the Jeffrey Modell Foundation for sponsoring this study, which was done in collaboration with lab alumni Prof Stephanie Humblet-Baron at the University of Leuven in Belgium. Check out the full paper at the Journal of Clinical Immunology!