Maintaining balance in the immune system

Key points:

• Researchers from the Turner lab have published the first description of the role of the ZFP36 family of RNA binding proteins in regulatory T cells (Tregs).
• Tregs are key to maintaining balance in the immune system and essential to preventing autoimmune disease.
• By the targeted deletion of Zfp36l1 and Zfp36l2 in Tregs in mice, the findings demonstrate that loss of these RNA binding proteins results in Tregs no longer being able to control other immune cell types, which results in inflammation.
• The data point to a key role of ZFP36L1 and ZFP36L2 in governing multiple cytokine responses in Tregs, including regulating the availability of the cytokine interferon-gamma, which activates immune responses, as well as being important in maintaining Treg stability.

Immunologists from the Institute have been the first to uncover a role for a family of RNA binding proteins in the function of regulatory T cells in the immune system. As their name suggests, regulatory T cells (Tregs) play a key role in modulating the immune system response, regulating the strength of the response by limiting the function of immune effector cells, such as ‘killer’ T cells. The research sheds important light on how the immune system maintains balance and forms the foundation for a greater understanding of age-related inflammation.

The Turner lab at the Institute is leading research into the role of RNA binding proteins in the function of the immune system to help us understand healthy ageing.

The group’s previous work has uncovered key knowledge about the role of the Zinc Finger Protein 36 (ZFP36) family of RNA binding proteins in the differentiation and activity of other T cell subsets but this is the first time their role in Tregs has been explored. Turner lab members Dr Beatriz-Sáenz-Narciso (postdoctoral researcher) and Dr Sarah Bell (senior research associate) led the latest research.

Sarah explained the importance and potential of understanding more about the regulation of the immune response by Tregs: “Regulatory T cells play a critical role in maintaining balance in the immune system. We know that low level chronic inflammation increases with age and the age-related decline in immune system function may contribute to this. In order to gain insights into how inflammation is regulated during ageing, and to inform the development of therapeutics to address chronic inflammation when this process goes wrong, it is important to determine how stability within the immune system is maintained.”

RNA binding proteins (RBP) have important roles in developmental biology, stress responses and inflammation and act by directly binding to messenger RNA. These proteins play an important role in the regulation of mRNA by modulating stability, degradation, localisation and translation, thus affecting gene expression. RNA binding proteins in the ZFP36 family regulate large numbers of genes in this way post-transcriptionally, with the best characterised being mRNAs which encode cytokines (molecular messengers) where ZFP36 proteins provide a crucial role in coordinating and limiting inflammation.

Using mice where two Zfp36 genes (Zfp36l1 and Zfp36l2) were deleted specifically in Treg cells, the research team found that these RBP play an essential role in Tregs to maintain immune homeostasis.

Mice with Treg cells lacking these RNA binding proteins showed an inflammatory phenotype, expanded populations of other immune cell types, elevated levels of molecular messengers (cytokines) that regulate the activity of other immune cells and increased levels of circulating antibodies.

Following their initial experimental findings, the team undertook a comprehensive analysis using sequencing technology to understand the landscape of gene expression effects resulting from the loss of ZFP36L1 and ZFP36L2. The team found that these RBP regulate a large number of genes that control pathways required for Treg cells to maintain immune homeostasis. These analyses guided the team to focus on the response to the molecular messengers interleukin 2 (IL-2) and interleukin 7 (IL-7) and to explore this further. They found that ZFP36L1 and ZFP36L2 have a role in enabling Tregs to response to IL-2 and IL-7, molecules involved in regulating immune cell responses.

Their analyses also uncovered that many aspects resulting from loss of ZFP36L1 and ZFP36L2 in Treg cells were connected to effects on another key molecular messenger, interferon-gamma (IFNg). The production of IFNg by immune cells can promote inflammation and findings from this work indicate that ZFP36L1 and ZFP36L2 function in Treg cells to regulate the production of this important cytokine.

“Tregs play an important role in fundamental aspects of controlling the immune response. We found that the loss of these RNA binding proteins caused a profound effect on the ability of Tregs to maintain immune homeostasis by connecting multiple pathways involved in modulating immune cell function.” explained Sarah.

Going forwards, the team will explore the ability of mice lacking the ZPF36 proteins to respond to infection and continue to widen their study of these RNA binding proteins in other T cell populations.

Dr Martin Turner, Head of the Institute’s Immunology research programme, commented: ”We have uncovered an important role for RNA binding proteins in supporting the vital function of Tregs in maintaining immune homeostasis. This discovery is important in learning more about the chronic inflammation associated with age-related health problems.”

This research was supported by the Institute’s animal facility (Biological Support Unit), Flow Cytometry, Genomics and Bioinformatics facilities and teams.

Notes to Editors

Publication reference

Sáenz-Narciso & Bell et al. (2025). ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis. Nature Communications

Press contact

Dr Louisa Wood, Head of Communications, louisa.wood@babraham.ac.uk

Image description

Representative images of sections (from L-R) of the lung, liver, and small intestine from control (upper panel) and knockout mice (lower panel) which displayed clinical signs. The arrows indicate accumulation of immune cells into these tissues.  Tissue sections were stained with haematoxylin and eosin. Scale bar represents 200mm.

Affiliated authors (in author order):

Beatriz Sáenz-Narciso , postdoctoral researcher, Turner lab

Sarah Bell, senior research associate, Turner lab

Louise Matheson, senior staff scientist, Turner lab

Ram K.C. Venigalla, postdoctoral researcher, Turner lab

Martin Turner, Head of the Immunology research programme

Research funding

The research was funded by strategic funding from BBSRC as an Institute Strategic Programme Grant and funding from the Wellcome Trust through an Investigator Award to Martin Turner.

Animal research statement

As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used mice to understand how loss of particular RNA binding proteins affected the cells of the immune system. In mice, the ZFP36 family of RNA binding proteins were genetically deleted in regulatory T (Treg) cells. Mice were carefully monitored for distress and limiting clinical signs (observable indicators of a health issue) and were humanely killed if they were assessed to have reached the limit for severity, with subsequent analyses of tissues. Mice not showing any clinical signs and matched controls, were humanely killed to provide blood and tissue samples for analysis. Mice were also crossed to generate animals that lacked one copy of the gene encoding interferon-gamma (IFNg) in addition to lacking ZFP36L1 and ZFP36L2 in order to show this cytokine was a driving force for the expansion of effector immune cells.

All mouse experimentation was approved by the Babraham Institute Animal Welfare and Ethical Review Body. Animal husbandry and experimentation complied with European Union and United Kingdom Home Office legislation.

Please follow the link for further details of our animal research and our animal welfare practices.

About the Babraham Institute

The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research 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 UKRI Biotechnology and Biological Sciences Research Council (BBSRC), 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.

About BBSRC

The Biotechnology and Biological Sciences Research Council (BBSRC) is part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.