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Meet Dr Alyssa Silva-Cayetano - Sir Michael Berridge Prize winner 2024

Dr Alyssa Silva-Cayetano, a former postdoc in the Linterman lab, was awarded the Sir Michael Berridge Prize for her leading contribution to the research described in the paper: . This work uncovered key changes to germinal centres that occur with age and lessen the immune response to vaccination. The knowledge of how age affects the germinal centre response can be used to inform approaches to develop ways to enhance vaccination response in older people, thereby protecting health.

Could you tell me a bit about your background and your career so far?

I grew up in both Peru and Australia. My family immigrated to Australia when I was ten years old and I studied Medical Science at the Australian National University in Canberra. I had an amazing Immunology lecturer in my last year of uni, Dr Aude Fahrer, who really inspired me to pursue a career in immunology.

I went on to do an Honours research year as part of my degree (the equivalent of an MPhil here) in Professor Carola Vinuesa’s lab, staying at the Australian National University. I studied the genetic basis of systemic autoimmune diseases and it was during this time that I was introduced to the germinal centre field and how important these structures are in different disease settings. I stayed on as a research assistant for an extra year to keep honing my laboratory skills and learn more about the germinal centre response.

When I decided I wanted to do a PhD in the germinal centre field, Carola was very supportive and put me in touch with Michelle who at the time was advertising a PhD position in her lab. I thought studying the germinal centre in the context of ageing would be an amazing opportunity so I was very grateful when I was able to get the position in her lab as part of the ENLIGHT-TEN Marie Curie program in 2016. I finished my PhD in 2019 and stayed on as a postdoc to keep investigating some of the interesting findings from the last year of my PhD.

Tell us more about the germinal centre and what you were trying to find out.

The germinal centre (GC) underpins the immune response to vaccination as it is the main source of long-lived antibody-secreting cells and it is known that this response declines with age resulting in reduced vaccination efficacy in older individuals. The initial goal of my research was to better understand the underlying mechanisms leading to this age-dependent decline in the GC response.

Towards the end of my PhD we were really starting to hone into the mechanisms of spatial dysregulation of T follicular helper cells (Tfh) in the aged germinal centre. T follicular helper cells are a type of T cell that are key influencers of B cells during their maturation in the germinal centre. Unfortunately, the end of my PhD coincided with the COVID-19 pandemic so activities on this project slowed down. Thankfully, Michelle facilitated the opportunity for us as a lab to be a part of the scientific response to the pandemic by conducting some of the preclinical tests for the Oxford-AstraZeneca vaccine in collaboration with Professors Sarah Gilbert and Teresa Lambe. In April 2020, myself and lab members Silvia and Will worked on testing this new vaccine in the Institute’s aged mice colony and were able to deliver a great data package that translated into humans when tested by Oxford’s clinical team. Both the human and mice studies outlined the need for a second dose of the vaccine to get better vaccination efficacy in older individuals.

Once the events of the pandemic started to wind down, I was able to continue my work on the aged germinal centre response and last year (2023) we were able to publish our findings on how spatial dysregulation of Tfh cells in the aged germinal centre impairs the response to vaccination. It was around this time when I left Michelle’s lab to make the switch into industry. I am now working at AstraZeneca in the oncology field but still with a focus on T cell biology and investigating novel T cell engagers.

How did it feel when you heard you had won this year’s Sir Michael Berridge prize?

I was surprised at first but also very grateful for the recognition of this work. This paper was nearly seven years in the making, and those were years of hard work and perseverance. I feel extremely blessed to have been able to do this work in the Linterman lab where I was able to grow and develop as a scientist. I’m also very grateful for all the members of the lab who helped me throughout the various stages of this research, especially at the point of revisions where I think pretty much every member of the lab pitched in with either experiments or data analysis to get this paper over the line.

Was there a key moment of discovery during this research?

There were essentially two key moments. The first being the moment we first observed that Tfh cells in GCs from aged mice were not polarised to the area known as the light zone and seemed to be mostly in the dark zone. It was a key moment because, at the time, we knew that Tfh cells had been previously described to also localise to the dark zone but there was nothing in the literature to indicate what their role in that compartment was or even if they had a role there. Once I confirmed these cells were high expressors of a protein (CXCR4) which is required for dark zone localisation), and when the computer modelling I performed in Professor Michael Meyer-Hermann’s lab indicated that Tfh cell positioning could have an impact on the GC response we had the extra confidence to investigate whether this observation could have a significant impact on the GC response in ageing.

The second key moment was when we created mice that lack CXCR4. In these mice we observed that the loss of CXCR4 polarised Tfh cells almost exclusively to the light zone of the germinal centre. Interestingly we also saw that this had a positive impact on light-zone specific cells called follicular dendritic cells (FDCs) and the affinity of GC B cells. This was a new discovery and alluded to a possible relationship between Tfh cell localisation and FDC expansion. These observations ultimately led us to try to supply T cells from young mice to the light zone of germinal centres in aged mice and we were able to demonstrate that the detrimental effects of ageing on the germinal centre, including the defects in FDC expansion, can be rescued in this way.

What have you been doing since you left the Institute?

Since leaving the institute, I’ve joined AstraZeneca as a Senior Scientist in the T cell engagers group within the Early Discovery Oncology department. It’s an exciting place to be at the moment and I have learnt a lot about antibody engineering and drug development. We are working on developing novel bispecific antibody treatments for cancer patients with high unmet need.

If you weren’t a scientist what would you be?

If I weren’t a scientist I’d love to be an archaeologist. It was almost the route I went down before I decided to pursue a Medical Science degree. I really loved studying ancient history in high school as I always thought there was something mysterious and intriguing about past civilisations. I think since I love to travel I would’ve enjoyed working in the field and also, my favourite movie growing up was The Mummy so I guess this somewhat romanticised archaeology in my mind but I’m very happy where I’ve ended up.

What have you taken with you from your time at the Institute? Do you have a favourite memory of being at the Institute?

I think my time at the Institute and at the Linterman lab has really helped shape both my work ethic and who I am as a scientist. It is clear from the scientific output of the many great labs at the Institute and the quality of its core facilities that it is a place that nurtures and values scientific growth and strives to maintain scientific excellence.

One of my favourite memories from my PhD was going to the 2019 B cell-T cell Keystone conference in Colorado with most of the lab. Many of us stayed together at an alpine cabin so it was a lot of fun to spend the days listening to great science talks, the late afternoons snowboarding and evenings having meals together; plus the scenery was amazing!

What do you get up to outside the lab?

Outside of the lab I really like to go social dancing. Most days of the week and on the weekend you’ll find me at a salsa, bachata or argentine tango social. It’s a great way to unwind, enjoy music and also exercise at the same time.

I also really love to cook, especially Peruvian food. I often try to recreate some of my grandmother’s cooking from fond memories of helping her in the kitchen. I find it both relaxing and somewhat cathartic to go through the motions of preparing a meal you love, which I suppose at times is not too dissimilar to experimental work in the lab but at least you get to eat your results.

What’s your favourite part of being a researcher?

The element of surprise and the constant learning opportunities.

Image description: Microscopy image of a germinal centre structure which is altered in aged mice (90-95 weeks old) compared to young mice (8-12 weeks old).