Maintaining balance in the immune system

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. 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.