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Preventing an identity crisis in the immune system

As with people, identity is vital to cells. When a cell loses its identity, it can stop working properly and a range of illnesses can result. The immune system, which protects our bodies from disease, includes cells with many different identities. When these cells lose their identity it can cause certain cancers or increase the risk of infections.

Complex networks of signals and genes create and maintain the identity of different cells. New research from �鶹��Ƶ, Cambridge and the has revealed how a protein called ZFP36L1 helps cells known as marginal zone (MZ B cells) to maintain their identity.

For cells, identity describes how they are adapted to have a specialised function. Blood cells are specialised for transportation, nerve cells for communication and the immune system fights infections. Each cell becomes specialised to do its job as a result of unique combinations of genetic instructions, which influence how the cell works.

MZ B cells play an important role in the early stages of preventing infection, by screening blood that passes through the spleen for signs of invading germs that might cause an illness. Without these cells, our body would be at much greater risk of illness.

In a in the journal , the team, led by showed that, by blocking the translation of certain genetic instructions, ZFP36L1 helps MZ B cells to keep the correct identity. By working together with and in Birmingham, the team have shown that ZFP36L1 ensures MZ B cells continue to communicate, move and interact correctly.

Many proteins that control the identity of cells act by interacting with DNA to switch genes on or off – silencing key genetic instructions. ZFP36L1 is different, it doesn’t shut down the genes but instead it stops their messages getting through to the rest of the cell.

Genes act as stores of information, but to have an effect on the cell they must be switched on. These active genes produce molecular messages called mRNA, which carry their instructions to other parts of the cell, where the instructions they carry are used to make proteins. Through proteins, genes influence how cells work. In MZ B cells, ZFP36L1 stops certain mRNA messages from getting through. This means the cells don’t produce certain proteins that could change their identity.

As lead author on the paper Rebecca Newman, now a post-doctoral scientist at the in London explained: “ZFP36L1 plays an important role in MZ B cells by controlling the levels of mRNA from genes such as IRF8 and KLF2. If ZFP36L1 is lost, MZ B cells leave the marginal zone of the spleen and many of them die.”

The paper’s senior author and Head of the at �鶹��Ƶ, Martin Turner said: “Our immune system contains many different types of cells with unique roles. Extremely complex processes govern the development and function of each of these cell types. This study adds to our understanding of the multi-level control over cellular identity for cells in the immune system.”

This work highlights the importance of proteins like ZFP36L1, which regulate multiple mRNA messages. Further understanding how ZFP36L1 and other similar proteins function and are controlled in MZ B cells could be important in autoimmune diseases – where the immune system attacks the rest of the body – and certain types of lymphoma.

This paper is also the focus of a Nature Immunology article titled "" by Palaniraja Thandapani, Beatriz Aranda-Orgilles and Iannis Aifantis from New York University.

Notes to Editors:

Publication Reference
Newman, R. et al., Maintenance of the marginal-zone B cell compartment specifically requires the RNA-binding protein ZFP36L1., Nat. Immunol. 18, 683–693 (2017).

Research Funding
This work was funded by a GSK-CASE studentship with additional support from the Biotechnology and Biological Sciences Research Council, The Medical Research Council and Bloodwise.

Press Contact
Dr Jonathan Lawson, Babraham �鶹��Ƶ Communications Manager
jonathan.lawson@babraham.ac.uk

Image Credit
Image source: Dr Becky Newman
Mouse spleen cells lacking ZFP36L1. Loss of ZFP36L1 causes marginal zone B cells (magenta) to move into spleen follicles, which consist of follicular B cells (blue) and surrounded by metallophilic macrophages (green).

Affiliated Authors (in author order):
Rebecca Newman, Helena Ahlfors, Alexander Saveliev, Alison Galloway, Robert Williams, Sarah Bell

About �鶹��Ƶ:
The receives strategic funding from the to undertake world-class life sciences research. It's goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on 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.

Animal research statement:
As a publically funded research institute and a signatory of the , �鶹��Ƶ is committed to engagement and transparency in all aspects of its research.  The research presented here used mice that were bred in the �鶹��Ƶ’s .  Lymphocyte numbers and functions were measured in adult mice.

All animal work was approved by �鶹��Ƶ Animal Welfare and Ethical Review Body, and carried out in accordance with the Animals (Scientific Procedures) Act 1986, under a UK Home Office project licence. This work adhered to the principles of the of animal research. Details of the mice used in these studies can be found in the methods section and the figure legends of the paper.

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