Meet Philippa Marrack: a Pioneer in T Cell Biology

International Day of Women and Girls in Science takes place every year on February 11, giving us the opportunity to celebrate the achievements of the inspirational women who have made great contributions to their field, and to encourage and embolden young female scientists to do the same. In this blog, we take a look at the career of Professor Philippa Marrack, an immunologist whose research helped shed light on T cell development and function.

A Promising Start

In the late 60s, Philippa started her career in immunology research with a PhD at Cambridge University, investigating a population of cells that had only been discovered a few years prior, which we would eventually come to know as T cells.

The discovery of T cells prompted a cascade of further questions about the biology of these cells and made for an exciting time for immunology research. In the early 1970s, Philippa decided to continue her research in this field by accepting a postdoc position at the University of California San Diego, USA. Not only was this a fortunate decision for Philippa’s professional life, but also for her personal life, as it was here that she met her current husband and scientific partner, John Kappler, with whom she has worked alongside ever since (Rennie 1992).

Introducing the T Cell Receptor

One of Philippa’s first ground-breaking discoveries related to the function and structure of the T cell receptor (TCR). By this point, researchers had recognized that T cells needed to bind both the antigen and also the major histocompatibility complex (MHC), the protein complex on the cell surface of host cells that presents the antigen, to become activated. Whether this was all controlled by one receptor or more was unknown.

Philippa, alongside her partner in life and science John, designed a clever experiment to figure this out, fusing together T cells that recognized different combinations of antigen and proteins of the MHC complex. As a simplified example, they fused a T cell which recognizes antigen 1 and MHC protein 1 with a T cell that recognizes antigen 2 and MHC protein 2. They then tried to stimulate the cells with the different combination of antigen 1 and MHC protein 2. When they saw that the fused cells didn’t respond to the mixed specificities, they realized that a single receptor must be able to see both parts (Kappler et al. 1981).

This was a massive advance in knowledge of the TCR, and in the early 1980s Philippa and John added even more information to our understanding of this receptor by identifying (alongside other research groups) the structure of the TCR.

Taming the Immune System

One of Philippa’s greatest scientific breakthroughs came about completely by accident. While investigating different TCRs in mice, they noticed that an entire population of mature T cells were missing in the periphery, though they could be found as an immature population in the thymus. The team realized that this was direct evidence of T cell tolerance, which describes how T cells that react too strongly to self-antigens are killed during their development before they get the chance to attack the body’s own tissues (Kappler et al. 1987). They came to understand that if these chaotic, self-targeting cells escape this tolerance, then they can trigger autoimmune diseases, like diabetes and multiple sclerosis. Marrack told Scientific American of T cell tolerance; “that’s the most important discovery we ever made” (Rennie 1992).

A Super Discovery

But Philippa's revolutionary discoveries didn’t stop there. In the 90s, Philippa and John identified a subset of extremely potent antigens that non-specifically activate T cells, which they aptly termed “superantigens”. To put things into perspective, with “normal” antigens, only about 0.0001% of T cells become activated, whereas exposure to superantigens can lead to the activation of up to 30% of T cells (Deacy et al. 2021). This then results in massive amounts of inflammation, cytokine release, and serious adverse effects. Philippa’s team showed that these superantigens were often the cause of food poisoning and toxic shock syndrome (Rennie 1992).

As Easy as ABC

More recently, Philippa’s research team has been interested in understanding why women are often more susceptible to autoimmune diseases than men. In 2011, they found that old female mice had a population of B cells that had previously been uncharacterized. They named these B cells age-associated B cells (ABCs) and showed that, when stimulated, these cells produce autoantibodies, suggesting a potential role for ABCs in autoimmunity (Rubstov et al. 2011).

All in all, it’s clear to see that Philippa is still a leader in her field. She has contributed to a lot of the knowledge that has now been integrated into textbooks and her work not only provides many of the fundamentals of T cell biology, but has also been a big contributor to our current knowledge of vaccines and autoimmune disorders in patients.  It is innovative and intelligent women like Philippa who inspire and motivate the next generation of female scientists!