Linterman lab at Babraham Institute uncovers reasons why our vaccine response declines with age

Scientists at the Babraham Institute have identified why our response to vaccinations declines with age in research that paves the way for the development of strategies to overcome the problem.

The researchers in the Linterman lab showed that age-related defects within immune structures called the germinal centre affect vaccine response.

But they also showed, in studies with mice, that these defects are reversible.

Understanding how our immune response changes with age is key to bolstering protection for those people most at risk.

We know that older people have lower levels of protection due to an age-dependent impairment in antibody production and their protection also wanes more quickly.

Our immune system responds to vaccination by creating specialised structures called germinal centres that produce the immune cells (B cells) that provide long-term protection by producing antibodies.

Dr Michelle Linterman and her group explored how the germinal centre alters as we age.

When functioning correctly, the germinal centre response requires the co-ordination of cellular interactions across both time and space.

Germinal centres are made up of two distinct regions called the light zone and dark zone, with some cells located in specific areas, and others that move between the zones.

B cells are shaped by their interactions in the dark zone first and then in the light zone.

Using mouse research, computer modelling and analysis of human vaccination data, the researchers showed changes to key interactors of B cells in the light zone of the germinal centre, known as T follicular helper (Tfh) cells, and changes to light-zone specific cells called follicular dendritic cells (FDCs), were crucial to the diminished vaccination response.

Dr Linterman, a group leader in the Babraham institute’s Immunology programme, said: “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."

This role for Tfh cells in supporting stromal cell responses to vaccines was previously unappreciated.

Using 3D computer modelling to simulate the loss of Tfh cells from the light zone and a reduced FDC network, the team recapitulated their findings, which strengthened their hypothesis that these two factors led to the reduced germinal centre response in aged mice.

Next, after identifying the dependencies between the cell types, the researchers used genetically modified mice to control the location of Tfh cells in the germinal centre.

This demonstrated that the defective FDC response was caused by loss of Tfh from the light zone.

And the team was 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.

Using data from human vaccination studies, the team 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,” said Dr Linterman.

The findings were published in Nature Immunology this week.