Settling the score on immune cell receptor function

Settling the score on immune cell receptor function

Key points:

  • Researchers have confirmed the dual action of a protein receptor in our immune response.
  • In addition to ensuring B cell survival, the protein receptor plays a critical role in generating a diversity of antibodies, essential for a healthy immune system.
  • Technology developed at the Babraham Institute allowed researchers to confirm the role of the receptor IL-7R in antibody diversity.
  • This research helps researchers to understand the full effect that age associated alterations to immune cell receptors have in our immune response in later life.

In a healthy immune system, B cells cut and paste together a couple of hundred genes in multiple different combinations, to produce the millions of different antibodies we need to identify and respond to each unique infection. Then, the B cells with the best match multiply to neutralise the threat. Research published today by researchers in the Immunology research programme, explains how the IL-7 receptor is key to producing as diverse a range of antibodies as possible, in addition to its more understood role in immune cell proliferation. This detailed understanding of B cell biology in mice provides a way of learning more about what happens in the human immune system, helping our understanding of immunodeficiencies and the effects of age on the immune system. 

The IL-7 receptor (IL-7R) is found on the surface of our immune cells and is essential for cell survival and multiplication. Some studies suggested an additional role for IL-7R, while others provided conflicting evidence. This new research applied state of the art technology to address the key questions: does IL-7R also control how B cells make many different antibodies, and how?

Dr Anne Corcoran and her research group began by investigating what happens to the immune system in the absence of the IL-7R. By comparing normal mice with mice lacking the gene that codes for IL-7R, they showed that B cells from these mice not only had poor survival, but also produced a more limited range of antibodies.

In the first step in making a unique antibody, cells combine genes from different stretches of DNA to create part of the antibody known as the immunoglobulin heavy chain. This process is called VDJ recombination. Molecular marks on the chromatin are thought to underlie the complex choice of gene segments. Changes in these ‘epigenetic’ marks control access to a different choice of genes.

Using a method developed at the Babraham Institute called VDJ-seq, the researchers were able to investigate the involvement of the IL-7R in this gene selection, studying millions of antibody genes and characterising the make-up of the VDJ segments in mice with and without the IL-7 receptor.

By looking closely at the access to V and D genes, Dr Corcoran and her team were able to find that IL-7R signalling specifically promotes antibody diversity in B cells by enabling large-scale access to the full repertoire of different DNA regions. Full access translates to a greater diversity in the mix-and-match mechanism of VDJ recombination creating the antibody heavy chain.

Dr Anne Corcoran said: “Ageing is associated with alterations in this receptor but the impacts on the immune system are not fully understood. Our studies indicate that impairment of B cell function may be a significant outcome of altered IL-7 signalling, due in part to a reduction in antibody diversity and a poorer response to infection. Recognising the importance of this could lead to wider inclusion of B cell function in diagnostic tests and therapeutic treatments. To achieve these benefits, these findings need to be validated in normal human subjects.”

Notes

Publication reference
A. Baizan-Edge et al. IL-7R signalling activates widespread VH and DH gene usage to drive antibody diversity in bone marrow B cells, Cell Reports

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

Image description:
Representation of VDJ genes for splicing featured in Weapons of Microscopic Destruction, an educational resource produced by the Babraham Institute.

Affiliated authors (in author order)
Amanda Baizan-Edge, former PhD student, Corcoran lab
Bryony Stubbs, former PhD student, Corcoran lab
Michael Stubbington, former PhD student, Corcoran lab
Daniel Bolland, former senior research associate, Corcoran lab
Kristina Tabbada, former Head of Sequencing
Simon Andrews, Head of Bioinformatics
Anne Corcoran, Group leader, Immunology research programme

Research funding
This research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC).

Additional/related resources
Anne Corcoran group page
News, 5th September 2018: How does ageing affect developing B cells?

Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. In this study, the gene that codes for the interleukin-7 receptor was deleted in these mice. B cells were collected from bone marrow of mice at 6-12 weeks of age. 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 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.

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.
Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. 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.