22/05/2023
Key points:
Understanding the ways our immune response changes as we age holds the key to designing better vaccines and boosting protection for people most at risk. Research published by Dr Michelle Linterman and her group today in Nature Immunology has explained that the organisation of the germinal centre, which is vital to the generation of longer-lived protection following vaccination, is altered in ageing. By demonstrating that these age-related changes can be reversed in mice, the research sets the foundation for interventions that bolster an effective vaccine response.
After a vaccination our immune system reacts by creating specialised structures called germinal centres that produce the immune cells (B cells) that provide long-term protection through the production of antibodies. Due to an age-dependent impairment in antibody production, older people have lower levels of protection from vaccination which also wanes more quickly compared to younger people. Protection by vaccination is essential to protect older people who become more susceptible to infections with age. Therefore, understanding how the age-related decline of the immune system can be reversed or mitigated is an important part of securing better health in later years.
The correct function of the germinal centre response requires the coordination of cellular interactions across time and space. Germinal centres are made up of two distinct regions – the light zone and dark zone, with some cells located in specific areas, and others which move between the zones. B cells are shaped by their interactions in first the dark zone and then in the light zone.
Through a combination of mouse research, computer modelling and analysis of human vaccination data, the Linterman lab research team were able to show that changes to key interactors of B cells in the light zone of the germinal centre, T follicular helper cells, and also to light-zone specific cells called follicular dendritic cells (FDCs), were at the heart of the diminished vaccination response.
Dr Michelle Linterman, a group leader in the Institute’s Immunology programme, explains “In this study we looked at what was happening to different cell types in the germinal centre, particularly the structure and organisation of the germinal centre across its two functionally distinct zones, to try and understand what causes the reduced germinal centre response with age.
"What we found is that the T follicular helper cells aren’t where they should be and as a result, antibody-producing cells lose essential selection cues. Surprisingly we also uncovered an unknown role for T follicular helper cells in supporting the expansion of follicular dendritic cells in the light zone after vaccination."
The team used 3D computer modelling to simulate the loss of Tfh cells from the light zone and a reduced FDC network, which recapitulate their findings and strengthened their hypothesis that these two factors were enough to be responsible for a suboptimal germinal centre response in aged mice.
Having identified the dependencies between the cell types, the researchers used genetically modified mice to control the location of Tfh cells in the germinal centre, demonstrating that the defective FDC response was caused by loss of Tfh from the light zone. Importantly, they were also able to correct the defective FDC response and boost the germinal centre response in aged mice by providing T cells that could correctly localise to the light zone.
The team also utilised data from human vaccination studies and found similar age-dependent changes in mice and humans.
“These findings give us a more complete picture of what the effects of age are on the germinal centre and vital insight into how we might address these in terms of developing effective strategies for enhancing vaccine response in older people” concluded Dr Linterman.
Publication reference Silva-Cayetano, A., et al. Spatial dysregulation of T follicular helper cells impairs vaccine responses in ageing, Nature Immunology (2023)
Press contact Honor Pollard, Communications Officer, honor.pollard@babraham.ac.uk
Image description: Microscopy image of a germinal centre structure which is altered in aged mice.
Affiliated authors (in author order): Alyssa Silva-Cayetano, former postdoctoral researcher, Linterman lab Sigrid Fra-Bido, former research assistant, Linterman lab Silvia Innocentin, research assistant, Linterman lab Alice Burton, postdoctoral fellow, Linterman lab Emily Watson, research assistant, Linterman lab Jia Le Lee, PhD student, Linterman lab Louise Webb, postdoctoral research scientist, Linterman lab William Foster, postdoctoral researcher, Linterman lab Ross McKenzie, research assistant, Linterman lab Alexandre Bignon, former postdoctoral scientist, Linterman lab Ine Vanderleyden, former PhD student, Linterman lab Edward Carr, former postdoctoral scientist, Linterman lab Danika Hill, former postdoctoral scientist, Linterman lab Michelle Linterman, Group Leader, Immunology research programme
Research funding This research was funded by the Biotechnology and Biological Sciences Research Council, part of UKRI, and the European Union’s Horizon 2020 research and innovation programme “ENLIGHT-TEN”.
Animal research statement: As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. All mice using in this research were bred and maintained at the Babraham Institute’s Biological Support Unit.
All mouse experimentation was approved by the Babraham Institute Animal Welfare and Ethical Review Body and animal husbandry and experimentation complied with European Union and United Kingdom Home Office legislation and local standards. Blood and tissues (inguinal lymph node, bone marrow) were taken from euthanised vaccinated and unvaccinated young adult (8-12 week old) and aged (90-108 week old) mice to assess germinal centre formation and count immune cell proportions. Young adult and aged mice were also used as donors or recipients of cells to understand the effect of age on B cells and to followed T cell localisation. Genetically modified mice were produced to generate mice with T cells lacking a particular cell receptor and these mice were vaccinated and later killed to collect tissue samples for analysis.
Please follow the link for further details of our animal research and our animal welfare practices. http://www.babraham.ac.uk/about-us/animal-research
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.
22 May 2023