Germinal Centers Become Dysfunctional with Age, Impairing the Immune Response

Complex systems that require different cell types to interact in intricate ways are found everywhere in the body, and these systems become dysfunctional with age. If all of the moving parts must perform correctly, then the system is vulnerable. It will start to fail the moment that any one of those component parts is sufficiently affected by the growing damage and signaling changes characteristic of aging. Here find an example of this point in the behavior of the germinal centers that form in well-trafficked locations such as lymph nodes, where immune cells can meet and exchange information. These germinal centers cease to efficiently function with age, reducing the effectiveness of the immune response, and researchers here identify the proximate cause of the problem.

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. 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.

Researchers were able to show that changes to key interactors of B cells in the light zone of the germinal centre, T follicular helper (Tfh) cells, and also to light-zone specific cells called follicular dendritic cells (FDCs), were at the heart of the diminished vaccination response. "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."

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 colocalize with FDCs using CXCR5 upregulation.