Unravelling the many mysteries of the immune system

Professor Gabrielle Belz is Chair in Immunology at the Frazer Institute at the University of Queensland, and a 2024 Australian Research Council (ARC) Laureate Fellow. She aims to understand how cells and the immune system function to protect us from illness and preserve life.

Too many people have to live with disease. But when you take the entire population, it’s actually quite a small number proportionally. It’s an intriguing question: why aren’t all of us sick all of the time?

I actually trained as a veterinary scientist – my main ambition was to do a PhD and become a veterinary specialist. But I always had a keen interest in how cells work and how the body prevents disease, and sort of got sidetracked and ended up in Peter Doherty’s lab. Yes, he’s the Australian (former veterinarian) who won the Nobel Prize for Medicine in 1995 for his pioneering work understanding how T-cells function in our immune systems.

We’ve made great leaps forward in understanding disease in recent years, but we also have massive gaps in this understanding. We often focus on just a few cell types and have not yet determined how the many different cells of the body work together.

For example, in the immune system we don’t fully understand why immunotherapy only works in 30 percent of people. The original concept was that we target a T-cell and get it to do something different, something positive, and that it then kills a tumour cell.

What we didn’t understand was the vast sets of other cells in the body, some immune, and some non-immune, that also express those receptors, and so when we target what we think is a T-cell, we’re also targeting the other cells. In addition, for the most part we have largely ignored cells such as epithelial cells and how they might communicate with immune cells. If we can understand the wiring of these various cells, we could use different sorts of approaches to change the outcome of the cells’ behaviour or even translate the signals into combination therapies that regulate multiple cell types.

Currently, we’re creating a positive response in the T-cell but in some cases a negative response in the other cells, so it cancels itself out and fails to have a positive effect.

It all comes down to really fundamental understandings of how all our cells work. This is pivotal in helping us translate therapies into the clinic.

A lot of my work now focuses on the epithelium, the tissue that covers the surfaces of organs such as our lungs and gut. In the past, we have thought about the epithelium as being a very uniform, unified layer of cells. But it turns out they’re very diverse and very specialised, and there are groups of those cells that specifically interact with immune cells. In fact, the epithelium is the first layer of signalling to the immune system, and it’s a massive gap in our knowledge.

My research looks at those initial cues that an epithelial cell gets from either extrinsic forces or pathogens or even commensal bacteria, how they interpret those signals, and how they convey them to the next layer of immune cells.

From a treatment point of view, we know those epithelial cells’ signals to the immune cells are the checkpoint that determines whether we develop disease, or whether we go about our business every day and don’t know that anything’s happened.

They’re highly diverse, they’re very specific to different regions, but we don’t know how they’re specialised for those regions, or when those specialisations are likely to be key determinants of the types of diseases that occur in those parts of the body. We don’t yet fully understand the nuts and bolts of how some cells are talking to other cells.

These epithelial cells are sending cues to what we call innate cells, which is a big family of cells that are all very specialised and do specific things and respond very quickly to damaging signals or threats. Then, depending on the signals they get, they tell adaptive immune cells, the B and T-cells, what to do.

Part of the reason that we don’t have disease like diarrhoea every day is because that epithelial set doesn’t bother the adaptive immune system until it’s absolutely necessary – an absolute pending threat that we need to get them activated. If we have them activated all the time, we’ll have immunopathology and if this is severe we might die. So there have to be these triggers and brakes to stop the immune system going off the rails.

Technology has really facilitated how we can look at these processes, and we wouldn’t be getting down to those micro levels if Covid hadn’t ushered in huge amounts of super-exciting technology.

This technology is very cool, but also incredibly challenging, because we now have way more data than we can even think about. Part of my challenge is to collaborate with bioinformaticians and systems biologists to find a common language for interpreting the data in a biological setting – some of the people I work may not have a great interest in what the cell is as they are more focused on the wiring rather than how they function or interact. But you talk to them about how the cell might work, and they’ll tell you how its signals might physically be detected. Somehow you have to work out how what they’re seeing mathematically makes sense with what you’re seeing cellularly.

I’ve worked with biological modellers both here and in the US, and the mathematics is very important for determining if your model is right or wrong. And it means you’ve got to sample enough points to understand the missing information in a model. It’s a massive puzzle.

I really love the challenge, and it holds great promise. If we understand the function of these other cells as well, we have a chance of using different sorts of therapies in much smarter ways, and that’s going to mean a much higher chance of positive outcomes.

This article was originally published in Cosmosmagazine.com