Dr. Sakaguchi’s quest to understand immune tolerance

The decision to study medicine was almost a given for Shimon Sakaguchi, who received his medical degree from the Faculty of Medicine at Kyoto University, Japan, in 1976, and a PhD degree at the same university six years later. 

“In my family, especially on my mother’s side, we have been rural doctors ever since the Shogun era. Many generations of my family, as well as many of my cousins, nephews and nieces, have all been doctors. Medicine was very familiar to me, and, well, it was not so difficult to decide to become a doctor,” Sakaguchi chuckles. 

Sakaguchi’s father had also strongly advised him to study natural sciences, particularly medicine. His father had been active in World War II and knew that humanities students were more likely to be recruited to the army and sent to war, and he didn’t wish that for his son. 

I was somehow influenced by that environment: Thinking about the “self”, the “non-self”, or even about concepts like tolerance, or the immune system and how it does good and bad things – I liked those kinds of existential questions. That was another influence I carried with me from my family.

“My father had majored in philosophy at the university, and there were lots of philosophy-related books at home. I was somehow influenced by that environment: Thinking about the “self”, the “non-self”, or even about concepts like tolerance, or the immune system and how it does good and bad things – I liked those kinds of existential questions. That was another influence I carried with me from my family,” he says.

Sakaguchi’s international path began with postdoctoral research in the US, at Johns Hopkins and Stanford (1983-1987). He moved with his wife, Noriko Sakaguchi, who also pursued a career in medicine and with whom he conducted research in the same lab for a period of time.

He then joined the Scripps Research Institute as an assistant professor in immunology, before returning to Japan in 1991 to work at the National Scientific Research Institute RIKEN. He became head of immunopathology at the Tokyo Metropolitan Institute of Gerontology, and later professor and chair of experimental pathology at Kyoto University’s Institute for Frontier Medical Sciences (1998-2011), where he served as its director from 2007. In 2011, his laboratory relocated to the University of Osaka, marking the next chapter of his leadership in immunology.

The Nobel Prize surprise

When the call came from the Nobel Assembly in Stockholm in October, to inform him that he had been awarded the prize together with Mary Brunkow and Fred Ramsdell, Sakaguchi was writing a paper in his office at the University of Osaka.

“Every year before the Nobel Prize is announced I get a call from some journalists asking if I’m expecting anything,” he says, when asked if the thought had crossed his mind that his research into peripheral immune tolerance might one day land him the Nobel Prize in Physiology or Medicine. 

“It was a very pleasant surprise, I felt really honored and almost elated. It has been a fantastic and memorable experience,” he recounts of receiving the news.

When Sakaguchi first proposed in 1995 that the immune system harbored an unknown class of cells dedicated to protecting the body from autoimmune diseases, many doubted him. The prevailing view was that immune tolerance arose when harmful immune cells were eliminated in the thymus, through a process known as central tolerance. 

Sakaguchi then closed the loop, proving that Foxp3 governs the development of the very cells he had uncovered. 

However, his discovery of regulatory T cells – known as Tregs – revealed another safeguard that prevents the immune system from turning against the body. Years later, Mary Brunkow and Fred Ramsdell identified the Foxp3 gene and were able to show that a strain of mice that carried a mutation in Foxp3 was particularly susceptible to autoimmune disease. Sakaguchi then closed the loop, proving that Foxp3 governs the development of the very cells he had uncovered. 

This year’s Nobel Prize in Physiology or Medicine celebrates their pioneering work on peripheral immune tolerance, a field of science that not only reshaped immunology but also paved the way for therapies in autoimmunity, cancer, and organ transplantation.

Shimon Sakaguchi received the Crafoord Prize in 2017. Photo: Simon Ungman

The future of the field

Where might the research into peripheral immune tolerance and immunology lead us from here? Sakaguchi explains that “the distance between basic immunology and clinical medicine is not long.” What this means is that if you find something in basic immunology it can easily be translated into clinical use, according to him.

“I hope that within ten years we’ll see good clinical advancement in two areas: One is how to augment immune responses, for example against cancer. And the other is how to suppress immune responses, for example in autoimmune diseases,” he says.

Within the area of cancer immunotherapy, removing or reducing Tregs in the tumor tissue and combining this therapy with current immune checkpoint blockade monoclonal antibodies should see vast improvements in the future, Sakaguchi muses.

“Currently the immune checkpoint blockade is effective in only 20–30 percent of cancer patients and then some cancers are refractory to such treatment. But within ten years, we can expect a higher rate of cure or treatment efficacy in a broader spectrum of cancers,” Sakaguchi says.

I think that the next cancer immunotherapy will be focused on the early stage of cancers.

He also explains that a great deal can be done to limit cancer metastasis, which currently causes 90 percent of cancer deaths: “I think that the next cancer immunotherapy will be focused on the early stage of cancers. If just after you have a cancer diagnosis, you start to somehow augment the immune responses against your cancer cells – just by reducing Tregs a bit – then you can prevent 90 percent of cancer metastasis. That would be a tremendous advancement in cancer immunotherapy,” he says.

On the flipside of the coin there is research into how to suppress immune responses in immunological diseases.

“Treg cell therapy is currently underway in various places around the world. As is research into how we can expand Tregs in vivo within our body, through treatments with certain cytokines or some drugs – and that kind of approach will advance in the future. Many pharmaceutical companies are very interested in the next generation of immunosuppressive drugs, which may be targeting Tregs,” he says.