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Natural born killers

Dr Arianne Richard talks about T cells, how knowing more about how they operate could open up new vaccines against viruses and new therapies for cancer, and why the ������Ƶ is the best place for her to tackle these questions.

While she’s relatively new to the ������Ƶ, Dr Arianne Richard, a tenure-track group leader in the Immunology programme since April 2022, feels at home in Cambridge. Born and brought up near Boston, she “migrated” down the east coast of the United States throughout her education, doing her undergraduate degree in Biochemistry at Columbia University, New York and spending the second half of her PhD at the National ������Ƶs of Health (NIH) in Washington, DC.

The first part of her PhD – through the NIH Oxford-Cambridge Scholars Program – involved two years in Cambridge. “That was my first introduction to Cambridge,” says Richard. “I loved the research culture and the atmosphere, so after my PhD I sought out a postdoc position at the University and was there for six years before starting my own group at the ������Ƶ.”

With a background in immunology and genomics, she selected the ������Ƶ for its strength in the field.

“The ������Ƶ has a such an incredible and cohesive immunology programme. I was particularly excited to join the programme here because they’re doing fascinating, cutting edge fundamental work on how immune cells function, particularly lymphocytes, which include the cells I’m interested in – T cells.”

A type of white blood cell, CD8 T cells are critical for how our immune system responds to infections as well as cancer. When these cells encounter virus or cancer cells, a cascade of events follows; the T cell divides many times but not all its offspring are the same. Some specialise as killer cells while others become the system’s memory. Killer T cells mediate this protective effect through their remarkable ability to recognise infected or cancerous cells. These they attach to via an ‘immunological synapse’ before firing tiny packets of toxic molecules into their target to kill it.

Richard studies T cells because as well as being killers, they are clever and complex. “They are part of the adaptive immune system, so as well as fighting current infection, they can create what we call immunological memory, which means they’re better at fighting the same infection when they meet it again in the future,” she says. How T cells decide whether to give rise to killer or memory progeny – and the factors that influence that decision – is what Richard wants to understand.

T cells do not exist in a vacuum, nor do they operate alone. Many factors will influence a T cell’s decision about its progeny, including where it is and whether any inflammation is present. And as well as making the right decisions for themselves, the T cells must also work together so the population as a whole responds appropriately. “That means T cells are integrating all these signals from many different components, acting collectively and interactively as they influence each other’s behaviour,” explains Richard.

The overarching question her lab is addressing is how do antigens – molecules on infectious or cancerous cells which trigger an immune response – and environmental factors influence T cell response? Because it’s such an intricate and important question, Richard is focusing on three key aspects: the influence of T cells’ location within the lymph node; how T cells respond to different strengths of antigen signalling; and how T cells signal to each other to regulate the immune response.

To do so, she’s using a raft of techniques, from powerful single cell technology – an area pioneered at the ������Ƶ – to protein changes and epigenetics. It’s challenging work, but understanding more about T cells’ decisions could open up new ways to influence those decisions, with important therapeutic or translational impact.

One potential benefit is development of T cell-targeting vaccines. These hit the headlines during the Covid-19 pandemic, because as the virus mutated, the neutralising antibodies produced by vaccines became less effective against the virus, but the same issue has also been a problem for influenza vaccines for decades.

“One potential route to a universal vaccine is to engage T cell responses in a greater way. These are often directed against parts of the virus under the surface, so although they don’t completely prevent infection, they can dramatically reduce the severity of an infection,” says Richard.

Other potential therapeutic benefits include manipulating T cell responses via immunotherapies – an area of huge interest in cancer treatment – and so-called checkpoint inhibitors, which effectively take the brakes off and reinvigorate T cell responses in the face of cancer.

Because the answers Richard is seeking cut across immunology, signalling and epigenetics – the ������Ƶ’s trio of programmes – she’s upbeat about what she can achieve. “The specialised science facilities here are phenomenal, which makes it possible to use techniques that I wouldn’t otherwise have dreamed of using,” she concludes. “And being able to collaborate across programmes with researchers in the same building is just so valuable. It’s a great place to be situated in order to think about these different angles to how these cells respond.”