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99�Ⱦò������µ�ַ scientists find clues to explain reduced vaccine response with age

Key points:

• The Linterman lab in the Institute’s Immunology research programme investigates why and how the body’s immune system becomes less robust with age.
• The group’s recently published research explores how age leads to the accumulation of precursor Tfh cells in both mice and humans.
• This detailed insight identifies specific molecules responsible for changing early Tfh cell differentiation and adds to fundamental understanding of the ageing immune system, which is essential for the development of novel strategies to boost health in older age.

While we might be more familiar with childhood vaccinations, adults receive a number of different vaccines later in life, for seasonal flu, pneumonia, and shingles. More recently, the COVID-19 pandemic has brought attention to the importance of understanding how different age groups react to vaccines. We know that as we age, our ability to generate an effective response to vaccination declines, and by understanding why, we could develop better vaccines. Dr Michelle Linterman, Immunology programme group leader, and her team investigate how our long lasting immunity changes with age. 

Germinal centres are hubs for long-lasting immunity and form in our secondary lymphoid tissues – in lymph nodes around the body and in the spleen. These specialised microsites are where different types of immune cells come together to form an immune response. An infection or vaccination initiates a highly coordinated series of events with specialised types of cell and different signalling pathways. Immune cells that leave the germinal centre are honed to target a particular virus, bacteria or pathogen with some of these cells becoming memory cells able to act quickly in response to future infections.

Within the germinal centre, T follicular helper (Tfh) cells identify the most effective B cells for dealing with a specific threat. These germinal centre Tfh cells form as a result of a multi-step process starting with T cell priming and two specialisation steps of differentiation to Tfh precursors and then further differentiation to germinal centre Tfh cells.

Research by the Linterman lab has previously shown that the effects of age on Tfh cells is partly responsible for the impaired immune response to vaccination seen in older individuals. Dr Louise Webb, a senior research scientist in the Linterman lab, led the group’s most recent research to further develop our understanding of why this is and to pinpoint the parts of the Tfh formation process that are particularly affected.

Various studies have tried to measure the effect of ageing on the generation of Tfh cells with conflicting results; some suggest that as we age more Tfh cells are created while others report lower numbers. First, the group sought to resolve these discrepancies. By distinguishing germinal centre Tfh cells from their precursors, the team found that although the levels of fully developed Tfh cells didn’t increase with age, levels of the precursor cells were higher in older mice following vaccination and in T cells from older people after stimulation.

With this new information, the team turned their attention to the molecules that form the signalling pathway leading to the creation of Tfh precursor cells. “To investigate the early stages of Tfh cell development, we took T cells from human volunteers and encouraged them to become Tfh cells, something that usually requires the addition of growth factors called cytokines. Surprisingly, T cells from older donors could create precursor Tfh cells without these factors.” Dr Webb explained. “We wanted to know more about this unusual finding.”

Dr Webb found that T cells from older people had enhanced expression of a transcription factor called RBPJ, and that this was responsible for the accumulation of Tfh cell precursors. By manipulating a binding partner of RBPJ, Dr Webb was able to implicate this mechanism in the formation of Tfh cell precursors in mice upon vaccination. Dr Webb summed up their key conclusion: “Although ageing results in the generation of more precursor Tfh cells due to increased expression of RBPJ, these cells accumulate and are unable to complete the next step to become fully developed Tfh cells. Without fully developed Tfh cells in the germinal centre the immune response is not as strong. Understanding the intricacies of immune cell development and how age affects this is key to developing approaches to maximise health into our later years.”

Experiments conducted in mice and cells from human donors lay the groundwork for our understanding of the immune system in people. These results give us a more detailed picture of what happens to the immune system as we age, and could help us to develop solutions to boost immune responses and treat diseases associated with immune system dysfunction in older people. The Linterman lab will continue to work towards their aim of understanding the events that happen in germinal centres after vaccination by expanding their research focus to other immune cell types.

Notes

Contact

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

Additional resources

Linterman lab group page

The Linterman lab’s recent research paper: L Webb, et al. Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ, Ageing Cell, 2020

News, 26 March 2020: How to boost immune response to vaccines in older people

News, 16 December 2020: Exploring the effects of age on the immune response to Oxford’s COVID-19 vaccine 

Image description

Tfh cells (green) within a germinal centre. Credit: Ine Vanderleyden, 99�Ⱦò������µ�ַ

Animal research statement

As a publicly funded research institute, the 99�Ⱦò������µ�ַ is committed to engagement and transparency in all aspects of its research. Animals are only used in 99�Ⱦò������µ�ַ research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The research presented here used mice in vaccination studies. The mice were bred and maintained in the 99�Ⱦò������µ�ַ Biological Support Unit. Mice were infected with influenza A virus under anaesthesia and then immunised. In a separate procedure, mice were injected with immune cells. Animal husbandry and experimentation complied with existing European Union and national legislation and local standards.

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