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Greater understanding of immune signalling molecule raises hope for improved clinical use

Key points:

• Researchers have identified source-specific effects of the signalling molecule interleukin 2 (IL2) on the immune response.
• IL2 is an important signalling molecule that has been harnessed as a biologic therapy for a number of diseases but can result in unwanted side-effects.
• This study, conducted using new mouse models, found that the immune response to IL2 is dependent on the cellular source of the IL2 production.
• Their new insight explains the link between IL2 treatments and side-effects, opening up the potential to apply this powerful immune modulator to optimise treatments while avoiding off-target effects.

A detailed update to our understanding of the key immune system signalling molecule interleukin 2 has been by researchers at the ����������̳. Their findings explain common side effects of IL2-based therapies, and identify potential new uses of IL2 as an immune-modulating biologic drug. This research was only possible thanks to a new mouse model which allowed researchers to control which immune cell types produced IL2. With further research, this understanding of the rules dictating which cells respond to IL2 could allow scientists to optimise autoimmune and cancer treatment while avoiding unwanted side-effects.

Dr Carly Whyte, lead author on the paper who undertook this research as a postdoctoral researcher in the Liston lab, said: "IL2 is a protein that is normally tightly regulated in the immune system because it has such strong effects. However, when IL2 is given as a therapeutic treatment, these normal restrictions on IL2 are overruled. By using mouse models, we have found that the presence of IL2 in certain zones of the immune system leads to some of the same side-effects that we see in human patients treated with IL2. We hope that by understanding more about how IL2 works in different zones, this treatment might be tailored to be more effective."

IL2 is involved in a large number of different communication networks in the immune system, being produced by a variety of cellular sources and affecting a diversity of cell ‘responders’. It is not only needed for maintaining regulatory T cells, which prevent our body’s immune system from attacking itself, but also CD8 T cells, which attack tumour cells and virus-infected cells. Owing to this dual functionality, IL2 has been harnessed to both promote an immune response, and limit one, depending on the target cells. Despite being actively explored in hundreds of ongoing clinical trials, the full therapeutic potential is currently limited by frequently-encountered side-effects.

This image shows the different cellular sources of IL2 and source-dependent cellular responders. Arrows indicate the production and uptake of IL2 by different cell types. Image credit: Sonia Agüera Gonzalez of Tenmei Illustration

Previous explanations for these side-effects were based on the high doses of IL2 when given as a biologic drug, but Prof. Adrian Liston and his team were able to demonstrate that the cell-type making IL2, and the location of those cells, dramatically change the consequences of IL2 exposure. Dr Kailash Singh, co-lead author, explains "Our genetically modified mouse models showed that the immune responses are varied depending on the source of IL2. Our findings revealed that the IL2 response is very much context-dependent, and is not solely due to the concentration of IL2."

Prof. Liston, a senior group leader in the Institute’s Immunology research programme, said: “This work changes the way we think about IL2 as a decades-old therapeutic molecule, demonstrating that it is not just the dose of the IL2 that matters, but also where it is located in the body. We’re increasingly aware of the therapeutic power of the immune system, and these findings provide a new avenue of investigation for designing biologic drugs.”

Dr James Dooley, joint senior author of the study, said: "The next generation of biologics will be smarter and tailored to the biology of the disease. This work teaches us that one route of smart design of IL2 is to target delivery to different parts of the body, potentially allowing us to drive very different therapeutic outcomes in patients."

Notes to Editors

Publication reference

Whyte et al. , Journal of Experimental Medicine, 2022

Press contact

Honor Pollard, Communications Officer, Honor.pollard@babraham.ac.uk

Image description: Header image is an abstract network of interconnected dots

����������̳ affiliated authors (in author order):

Carly Whyte, former postdoctoral researcher, Liston lab

Kailash Singh, visiting fellow, Liston lab

Oliver Burton, senior scientist, Liston lab

Meryem Aloulou, visiting fellow, Liston lab

Lubna Kouser, postdoctoral research scientist, Liston lab

Rafael Valente Veiga, postdoctoral research scientist, Liston lab

Amy Dashwood, PhD student, Liston lab

Hanneke Okkenhaug, Deputy manager, Imaging facility

Alena Moudra, postdoctoral research scientist, Liston lab

Samira Benadda, visiting scientist, Liston lab

Orian Bricard, postdoctoral research scientist, Liston lab

Stephanie Lienart, research fellow, Liston lab

Pascal Bielefeld, visiting scientist, Liston lab



Carlos Roca, former senior scientist, Liston lab

Francisco Naranjo, visiting scientist, Liston lab

Lubna Kouser, postdoctoral research scientist, Liston lab

James Dooley, senior staff scientist, Liston lab

Adrian Liston, Immunology programme group leader

Research funding

This research was supported by the VIB, the European Research Council, the Alzheimer’s Association and the Biotechnology and Biological Sciences Research Council (BBSRC).

Animal research statement:

As a publicly funded research institute, the ����������̳ is committed to engagement and transparency in all aspects of its research. Researchers created a genetically modified mouse to control production of IL2. Modified mice were compared to wild type mice. Spleen, lymph nodes, lung tissues and bone marrow were collected from the mice for analysis. The researchers also created chimeric mice by injecting bone marrow from genetically one mouse into another. Some mice were treated with radiation to knock out their immune system before bone marrow cells were given intravenously.

All experiments were performed in accordance with the University of Leuven Animal Ethics Committee guidelines, the ����������̳ Animal Welfare and Ethics Review Body or the Animal Care Committee at Maisonneuve-Rosemont Hospital Research Centre. Animal husbandry and experimentation complied with existing European Union and national legislation and local standards.

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About the ����������̳

The ����������̳ undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. ����������̳ focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

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