Manipulating brain Tregs to protect against neuropathology

From the GlobalImmuno Talks 20222:

2021 Golden Pipette

The Golden Pipette has a long and illustrious record. Awarded at every lab retreat in recognition of a single very cool result, the Golden Pipette has been handed down through generations of talented scientists. This year the Golden Pipette was awarded to.... Ntombizodwa Makuyana, for her exciting new approach to creating an anti-inflammatory environment in the lung. Well done Tombi, for a stunning first year PhD result!

Responding to the COVID crisis

As well as exposing weaknesses in healthcare systems and supply chains, the coronavirus pandemic has underscored the importance of fundamental research and collective effort. During 2020, scientists rose to the challenge of developing new vaccines and effective treatments for Covid-19. Institute immunologists Dr Michelle Linterman and Professor Adrian Liston describe how their labs responded and the lessons we must learn.

In the early days of the coronavirus pandemic, as lockdowns loomed, workplaces closed and travel slowed to a trickle, Dr Michelle Linterman was certain of one thing – she wanted to make her group’s expertise available to the global vaccines effort.

Among those working on a vaccine against SARS-CoV-2 (the coronavirus that causes Covid-19) was Dr Teresa Lambe at the Jenner Institute in Oxford. “I already knew Tess, so once it became clear they had a vaccine candidate, my first instinct was to ask her what we could do to help,” Linterman recalls.

As an immunologist, Linterman’s work focuses on how the immune system responds to vaccines. In particular, she wants to understand why older people respond less well to vaccines, something she studies using human vaccination studies and in aged mice. “I thought the most useful thing was for us to offer something that nobody else could contribute quickly – and that was our ability to use aged mice as a pre-clinical test of how this vaccine is likely to work in an ageing immune system,” she says.

When Lambe said yes, Linterman set up trials to compare immunological responses to the Oxford/AstraZeneca vaccine in young and aged mice, and discovered that although aged mice responded more poorly than young mice to a single dose, after two doses of the vaccine, the immune responses were very good in both groups.

The study helped both institutes. For the Jenner, it showed two doses of the vaccine would give good protection against infection in all adults. For Babraham, it provided new insights into vaccine responses at a cellular and molecular level, expanded research into new vaccine platforms and led to new collaborations. Most importantly, it illustrated the value of publicly-funded research.

“Because we’re funded by the BBSRC – in other words the tax payer – it was incredibly important to use our knowledge and expertise to contribute to vaccine development in the midst of the pandemic,” she says.

Fellow immunologist Professor Adrian Liston also stepped up to the mark, using his research to help clinicians make the best treatment choices for Covid-19 patients and his communication skills to provide accurate information to journalists and the public.

“We need to develop good systems for treating emerging viruses before we know much about them, which is something my lab is working on,” explains Liston. “We are coming up with treatments that are vaccine agnostic, treatments that will work for most viruses with the potential to become pandemic, regardless of the actual virus.”

Liston’s group is also interested in systems immunology – exploring what makes people’s immune systems so different from each other.

 This variation has been graphically illustrated during the pandemic, some people experiencing mild symptoms while others died. “Diversity is intrinsically important to the immune system. It’s the most genetically-diverse system in the human body, and there are other factors at play, such as age, gender and weight,” he explains.

Being so close to events has taught Liston and Linterman many lessons – lessons, they say, that are vital for political leaders to learn. First, zoonoses (diseases spread between animals and humans) with pandemic potential are far from rare events. “They occur every couple of years,” says Liston. “We’ve had coronavirus outbreaks before, like SARS and MERS; they happen like clockwork. In the previous outbreaks we had better luck and better preparation. These are things we must prepare for.”

Secondly, we must guard against complacency. “If we pat each other on the back for a job well done, and then slash science budgets, the next outbreak will be as bad as this one,” he warns. “We must fund surveillance as well as immunology and virology research, because if you scale down this science it takes a decade or more to rebuild that intellectual capital.” This preparation extends to supporting fundamental research in a broad range of areas. “We need to fund fundamental research because you’re never sure which bit of it will save you in the future,” says Linterman.

 Third, a global approach to research, and funding to support this, is essential, because scientific discoveries are not bounded by borders, adds Linterman: “One of the reasons the Oxford vaccine was developed so fast was because of years of work on Ebola and MERS using the same adenoviral vaccine vector.”

As vaccines are rolled out, and countries emerge from lockdown, we might usefully reflect on what we would have done without a vaccine. It’s a scenario that frightens Linterman. “There wasn’t another exit strategy,” she says. “The vaccines are great, far better than we expected. But there are pathogens that we don’t have good vaccines for. For me, that’s the scary thing. We’re lucky the vaccines are so effective – but that doesn’t mean the same will be true for the next pandemic.”

This feature was written by Becky Allen for the Annual Research Report 2019-2020.

Public Engagement award for the VirusFighter team

Congratulations to the VirusFighter team for winning the Babraham Institute Public Engagement Award! VirusFighter is the reincarnation of VirusBreak. Over the last year I've worked with the PhD students in our lab, Amy Dashwood, Ntombizodwa Makuyana and Magda Ali, together with lab alumni David Posner, to create missions for VirusFighter - allowing the player to be Prime Minister of the UK during different virus outbreaks. GameDoctor created the interface, with liason via the PE team here at the Babraham Institute.

Congrats to Amy, Tombi, Magda and David - a huge contribution to scientific communication, and all during the first year of their PhDs!

 

Congratulations to Ntombizodwa Makuyana

Congratulations to Ntombizodwa Makuyana, for winning the Babraham Institute prize for best poster by a first year PhD student!

A great start to a high potential PhD!

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.

Congratulations Dr Steffie Junius!

Congratulations Dr Steffie Junius, for achieving a successful PhD! Steffie has just completed an ambitious graduate program, studying the plasticity and fragility of regulatory T cells. It has been a pleasure watching Steffie grow into a successful scientist. Like every PhD, it had its ups and downs, its challenges and highlights, and I'm incredibly proud of how Steffie handled the entire process. I just wish I could have been there in person to celebrate her big day!

Dr Junius is now moving on to an exciting position as post-doctoral researcher at Janssen. Her major thesis work on regulatory T cell plasticity will hopefully come out soon - it is an elegant study with major implications for the design of cell therapy approaches using regulatory T cells. Well done Steffie!