Title: Does lymphoid fibroblast senescence contribute to poor vaccine responses in older persons?
Funder: Dunhill Medical Trust

Abstract: With advancing age the immune system becomes less functional, culminating in increased susceptibility to infections in older persons. Vaccination is an excellent public health intervention that limits infection-related morbidity and mortality, however vaccines are often ineffective in older persons, leaving this at-risk group vulnerable to infections. The fundamental biology that underpins the decline in immune function and vaccine responsiveness is yet to be fully understood, and my lab aims to elucidate these clinical challenges with the view to improving vaccine responses. The generation of long-lived protective immunity is dependent on the germinal centre (GC) response, a specialised reaction that occurs in secondary lymphoid organs during immunisation. GC formation supports the production of memory B cells and plasma cells that secrete high affinity antibodies that provide humoral protection from infection. The GC response requires complex interactions between several immune cell types, brought together upon a network of fibroblasts that coordinate their functions in time and space. My recent research has shown that lymphoid fibroblasts are a key determinant of the impaired GC function in aged mice, however the mechanisms that underpin these phenomena are unknown. I have preliminary data suggesting that aged mouse lymphoid fibroblasts have features that are reminiscent of senescence, an age-associated cellular phenotype that renders cells unresponsive to stimulation and contributes to tissue ageing. In this project, I will establish whether human lymphoid fibroblasts become senescent with age, how this ageing process affects the phenotype of lymphoid fibroblasts, and whether it impacts on their ability to support the GC response. I will do this by developing an in vitro system to study human lymphoid fibroblasts and determining how senescence changes their function. I will then explore how senescence may alter the ability of lymphoid fibroblasts to support B cells to produce antibodies using a co-culture system. In the final aim I will develop a 3D organoid model of human GCs, which will allow me to investigate key aspects of the human GC response, including how this is altered in senescence/ageing. Overall, this project will allow me to build a new area of research within my group, establishing essential protocols for studying human GCs, as well as generating preliminary data for future grant applications aiming to understand the mechanisms that impair the GC response in ageing.

Lay abstract: Advancing age is associated with the decline in the functions of many body systems, and this includes the immune system. This can be easily seen with the recent coronavirus pandemic, where older people are substantially more likely to become very ill, or die, from SARS-CoV-2 infection, and we see similar pathology with other infections, such as influenza. The coronavirus pandemic has also shown us that vaccinations, when available, are very effective at limiting bad outcomes from infection, however this is not always the case with older people. Some older people don’t respond very well to vaccines, meaning they are less protected from infection, and we don’t really understand why this is the case. If we could better understand why vaccines don’t work in older people then we could engineer vaccines that can target what’s wrong to get a better response from the vaccine. This would mean that older people are better protected from severe infections and can lead healthier lives. My laboratory is trying to understand why older people do not respond well to vaccines. We have recently found, using mice, that the environment to which immune cells are exposed has a significant impact on how well they can generate a vaccine response: young immune cells aren’t very good at responding to vaccines when they are in an old environment. We have also found that the lymph node environment seems to become non-responsive with increasing age, and we now think that this may be an important reason as to why vaccines sometimes don’t work well in older people. In this project, I want to extend these findings and determine whether the environment of human lymph nodes is similarly affected by age, and whether this impacts on the vaccine response. This study will determine whether the lymph node environment is switched off (“senescent”) with advancing age, and whether this impairs the immune response. These proof-of-concept findings will form the basis for future studies, which will delve into why the aged environment cannot support the immune response. Ultimately, this research will inform ways to improve vaccine design in order to elicit better vaccine responses in at-risk older people.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION;GENERIC HEALTH RELEVANCE